|
Displacement of [3H]tamoxifen from antiestrogen binding site (AEBS)
|
Homo sapiens
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Phenolic metabolites of clomiphene: [(E,Z)-2-[4-(1,2-diphenyl-2-chlorovinyl)phenoxy]ethyl]diethylamine. Preparation, electrophilicity, and effects in MCF 7 breast cancer cells.
Year : 1989
Volume : 32
Issue : 1
First Page : 192
Last Page : 197
Authors : Ruenitz PC, Arrendale RF, Schmidt WF, Thompson CB, Nanavati NT.
Abstract : The triarylethylene antiestrogen clomiphene was previously shown to undergo biotransformation to an active metabolite, 4-hydroxyclomiphene, and to 3-methoxy-4-hydroxyclomiphene plus the respective regioisomers of these, 4 and 5. We now report the synthesis and further chemical and biochemical studies on 3-5. Coupling of 4-[2-(diethylamino)ethoxy]benzophenone with either 4-(benzyloxy)benzaldehyde or its 3-methoxy analogue 11b in the presence of titanium, followed by chlorination and deprotection of the intermediate triarylethylenes, gave 4 and 5, respectively. Condensation of benzylmagnesium chloride with the (2-methoxyethoxy)methyl (MEM) ether of 4-[2-(diethylamino)ethoxy]-3'-methoxy-4'-hydroxybenzophenone, followed by mild acid treatment, afforded deschloro 3 due to facile MEM ether hydrolysis. Acetylation of this, followed by chlorination and deacetylation, gave 3. Compounds 4 and 5 reacted readily with nucleophiles. In particular, 2-mercaptoethanol reacted with 4 to afford deschloro vinyl thioether 13 as suggested by NMR spectral studies, a result that implicated allene-quinone 14 as the electrophilic species produced in solution from 4. Antiestrogen binding sites and estrogen receptors from MCF 7 human breast cancer cells interacted with 3 and 5 with affinities comparable to those of tamoxifen and 1, respectively; 5 was shown not to bind irreversibly with these sites. Inhibition of MCF 7 cell proliferation by 3-5 at 5 microM concentrations (76%, 57%, and 49%, respectively, relative to drug-free controls) compared favorably to that observed with 5 microM 1 (80%). These results suggest that 3-5 as well as 2 may contribute to the antiestrogenic effects of 1.
|
Binding affinity towards antiestrogen binding site AEBS
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 1. Receptor interactions.
Year : 2003
Volume : 46
Issue : 6
First Page : 883
Last Page : 908
Authors : Jordan VC.
|
Percent of inhibitory activity against proliferation of BT-20 cells in presence of TPE at 10e-5 M concentration.
|
Homo sapiens
|
56.0
%
|
|
Journal : J. Med. Chem.
Title : Effect of triphenylacrylonitrile derivatives on estradiol-receptor binding and on human breast cancer cell growth.
Year : 1989
Volume : 32
Issue : 9
First Page : 2092
Last Page : 2103
Authors : Bignon E, Pons M, Crastes de Paulet AC, Doré JC, Gilbert J, Abecassis J, Miquel JF, Ojasoo T, Raynaud JP.
Abstract : In a study of a series of 26 triphenylacrylonitrile derivatives (TPEs), we investigated the influence of several possibly interrelated factors on the proliferation of human breast cancer cell lines. (1) Chemical substituents: the test compounds were for the most part para-hydroxylated with increasingly bulky hydrophobic and/or basic side chains [isopropyloxy or (diethylamino)ethoxy] or standard reference compounds. (2) Relative binding affinities (RBAs): they competed diversely for [3H]estradiol (E2) binding to calf uterus cytosol and little, if at all, for binding to the [3H]tamoxifen-labeled antiestrogen binding site (AEBS) in lower speed supernatant. A multiparametric comparison of RBAs recorded for calf, rat, and mouse uterus cytosol estrogen receptor (ER) revealed a possible influence of species-specific receptor conformation and/or environment on binding. (3) Estrogen/antiestrogen potency: their stimulation and inhibition of the proliferation of the ER-positive human breast cancer cell line (MCF7) was measured. Compounds with only hydroxy substituents stimulated proliferation more markedly than methylated derivatives and had a maximum effect at 10(-11)-10(-6) M. Stimulation was related to the RBA for ER. Compounds with isopropyloxy or (diethylamino)ethoxy side chains only weakly stimulated MCF7 cell growth and more powerfully antagonized E2-promoted growth. The extent of inhibition depended upon the bulk of the side chain and could be reversed by 10(-7) M E2. Within the same concentration ranges, the test compounds were without effect on the BT20 ER-negative cell line. (4) Cytostatic and/or cytolytic activity: most compounds could arrest the proliferation of both MCF7 and BT20 cells at concentrations above 3 x 10(-6) M. This activity was thus independent of ER. Nevertheless, those compounds with a charged hydrophobic side chain, which were the most powerful antagonists of E2-promoted cell growth, were also the most cytotoxic. The overall results for all molecules on all parameters were submitted to a multivariate analysis (correspondence analysis) which revealed the progressive influence of increasing substitution by hydroxy and more bulky groups on the generation of antagonist activity and cytotoxicity.
|
Inhibition of Calmodulin activation of cyclic nucleotide phosphodiesterase
|
Homo sapiens
|
44.0
%
|
|
Journal : J. Med. Chem.
Title : Antiestrogens. 3. Estrogen receptor affinities and antiproliferative effects in MCF-7 cells of phenolic analogues of trioxifene, [3,4-dihydro-2-(4- methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]- phenyl]methanone.
Year : 1992
Volume : 35
Issue : 5
First Page : 931
Last Page : 938
Authors : Jones CD, Blaszczak LC, Goettel ME, Suarez T, Crowell TA, Mabry TE, Ruenitz PC, Srivatsan V.
Abstract : Benzothiophenes 3 and 4, derived from the acrylophenone antiestrogen trioxifene (2), are characterized by high estrogen receptor (ER) affinity and low residual estrogenicity compared to tamoxifen (1a). In order to characterize further the growth suppression mechanism for these structural types we have prepared structural variants of 2 bearing hydroxy groups positioned to maximize ER affinity. Thus, dihydronaphthalenes 5 and 6 and benzofluorenes 7 and 8 were prepared and studied in MCF-7 human breast cancer cells, in comparison with 3 and 4. All compounds were powerful suppressants of cell growth, with 50% inhibition ranging from 4.5 to 160 nM. Greatest potency was seen with diphenols 6 and 8. These compounds had intracellular ER affinities ranging from 0.2 to 4.1% of that of estradiol, suggestive of a potential for partial agonist effects. Simultaneous exposure of cells to 0.1 microM concentrations of estradiol and 3 or 4 did not affect the degree of growth inhibition seen with 0.1 microM 3 or 4 alone. Partial reversal of inhibition occurred when 0.1 microM 5-8 were each accompanied by 0.1 microM estradiol. Under these conditions complete reversal of growth inhibition has been found with 1a, 1b, and other triarylethylenes. Calmodulin, a putative target for triarylethylenes, and which is antagonized by 1a, was shown to interact weakly with 7 and 8 and not at all with 3-6. These results suggest that MCF-7 cell growth suppression by 3-8 may be due to interaction with unidentified receptors besides ER and extend earlier findings indicating that events occurring after interaction of these compounds with ER differ from those of triarylethylene antiestrogens.
|
Inhibition of [3H]thymidine incorporation into EL4 cell proliferation
|
Mus musculus
|
535.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 2-(p-chlorobenzyl)-3-aryl-6-methoxybenzofurans as selective ligands for antiestrogen-binding sites. Effects on cell proliferation and cholesterol synthesis.
Year : 1992
Volume : 35
Issue : 8
First Page : 1330
Last Page : 1339
Authors : Teo CC, Kon OL, Sim KY, Ng SC.
Abstract : A series of nonsteroidal compounds, 2-(p-chlorobenzyl)-3-aryl-6- methoxybenzofurans derived from the 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones has been synthesized. The key steps in the synthesis were reactions of 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones with the arylorganometallic reagents followed by dehydration of the resulting carbinols. The benzofurans are ligands for antiestrogen-binding sites (AEBS) and display no significant interaction with the estrogen receptor (ER). All bind to AEBS with equivalent or greater affinity than tamoxifen. These compounds decrease [3H]thymidine incorporation in AEBS-containing EL4 lymphoid cells and MCF7 breast cancer cells in a concentration-dependent manner between 10(-8) and 10(-6) M and are generally more inhibitory than tamoxifen. In contrast, they have no effect on [3H]thymidine incorporation by an AEBS-deficient variant of the MCF7 cell line, RTx6. The present findings of (1) selective and high affinity binding of the benzofurans to AEBS, (2) their concentration-dependent inhibition of [3H]thymidine incorporation in AEBS-containing cells, and (3) their lack of antiproliferative effect in an AEBS-deficient cell line suggest a functional role for AEBS in mediating the antigrowth effect of these compounds. Two of the more active benzofuran compounds also significantly inhibited de novo cholesterol biosynthesis in EL4 cells which lack ER. This effect could be obtained after 5 h of treatment and preceded significant loss of cell viability. This is the first demonstration that selective ligands of AEBS (other than the known nonsteroidal antiestrogens) interfere with cholesterol biosynthesis-an action that may contribute to their antigrowth effect.
|
Antiestrogenic activity in MCF-7-2a cells as concentration required to reduce estradiol effect by 50%
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigations on estrogen receptor binding. The estrogenic, antiestrogenic, and cytotoxic properties of C2-alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes.
Year : 2002
Volume : 45
Issue : 24
First Page : 5358
Last Page : 5364
Authors : Lubczyk V, Bachmann H, Gust R.
Abstract : C2-Alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes were synthesized and assayed for estrogen receptor binding in a competition experiment with radiolabeled estradiol ([3H]-E2) using calf uterine cytosol. The relative binding affinity decreased with the length of the side chain R = H (3a: 35.2%) > Me (3b: 32.1%) > Et (3c: 6.20%) approximately CH2CF3 (3d: 5.95%) > n-Pr (3e: 2.09%) > Bu (3f: 0.62%). Agonistic and antagonistic effects were evaluated in the luciferase assay with MCF-7-2a cells stably transfected with the plasmid ERE(wtc)luc. All compounds showed high antiestrogenic activity without significant agonistic potency. The comparison of the IC(50) values for the inhibition of E2 (1 nM) documented the dependence of the antagonistic effects on the kind of the side chain: 3a (IC50 = 150 nM), 3b (IC50 = 30 nM), and 3f (IC50 = 500 nM) were weak antagonists, while 3c (IC50 = 15 nM), 3d (IC50 = 9 nM), and 3e (IC50 = 50 nM) were full antiestrogens and antagonized the effect of E2 completely. The most active compound 3d possessed the same antagonistic potency as 4-hydroxytamoxifen (4OHT: IC50= 7 nM) without bearing a basic side chain. 3d as well as all other 1,1-bis(4-hydroxyphenyl)-2-phenylalkenes were not able to influence the proliferation of hormone dependent MCF-7 cells despite the antagonistic mode of action. In this assay tamoxifen (TAM) and 4OHT reduced the cell growth concentration dependent up to T/C(corr) = 15% and 25%, respectively.
|
Antiproliferative activity against estrogen receptor positive MCF-7 human breast cancer cell line at a dose of 10e-5 M. (p<0.05)
|
None
|
71.9
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes as pure antiestrogens.
Year : 1991
Volume : 34
Issue : 2
First Page : 842
Last Page : 851
Authors : Day BW, Magarian RA, Jain PT, Pento JT, Mousissian GK, Meyer KL.
Abstract : A series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs) was synthesized and evaluated as pure antiestrogens. Addition of 4-methoxy- or 4-(benzyloxy)phenyl Grignard reagents to p-methoxy, p-benzyloxy, or unsubstituted deoxybenzoins, followed by dehydration of the resulting carbinols produced a mixture of E and Z olefins, which were reacted with dichlorocarbene to give O-protected DTACs. The E and Z isomers were separated by fractional crystallization and the central or geminal phenyl ring was deprotected to provide phenolic DTACs. Alkylation with (N,N-dimethylamino)ethyl chloride yielded basic cyclopropanes. Two chlorodiarylindenes were isolated as thermolysis products of the DTACs, and one was converted to a phenol by hydrogenolysis. All DTACs and indenes were competitive inhibitors of [3H]estradiol binding in the immature rat uterine cytosol receptor assay, with relative binding affinities of 0.1-3.6% of estradiol. None of the new compounds were estrogenic in the 3-day immature mouse uterotrophic assay at doses up to 750 micrograms. In the 3-day immature mouse antiuterotrophic assay, five DTACs with either a methoxy (5a), benzyloxy (4d, 5c), or (dimethylamino)ethoxy (7a, 7b) central ring side chain produced significant decreases in uterine weight at doses up to 750 micrograms. One compound, (Z)-1,1-dichloro-2-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- methoxyphenyl)-3-phenylcyclopropane (7b), elicited a dose-dependent decrease in vivo comparable to MER 25. These same five compounds, as well as the lead compound Analog II, were active in vitro against the estrogen-dependent MCF-7 human breast tumor cell line in a dose-dependent fashion.
|
Antiproliferative activity against estrogen receptor positive MCF-7 human breast cancer cell line at a dose of 10e-7 M. (p<0.05)
|
None
|
51.8
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes as pure antiestrogens.
Year : 1991
Volume : 34
Issue : 2
First Page : 842
Last Page : 851
Authors : Day BW, Magarian RA, Jain PT, Pento JT, Mousissian GK, Meyer KL.
Abstract : A series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs) was synthesized and evaluated as pure antiestrogens. Addition of 4-methoxy- or 4-(benzyloxy)phenyl Grignard reagents to p-methoxy, p-benzyloxy, or unsubstituted deoxybenzoins, followed by dehydration of the resulting carbinols produced a mixture of E and Z olefins, which were reacted with dichlorocarbene to give O-protected DTACs. The E and Z isomers were separated by fractional crystallization and the central or geminal phenyl ring was deprotected to provide phenolic DTACs. Alkylation with (N,N-dimethylamino)ethyl chloride yielded basic cyclopropanes. Two chlorodiarylindenes were isolated as thermolysis products of the DTACs, and one was converted to a phenol by hydrogenolysis. All DTACs and indenes were competitive inhibitors of [3H]estradiol binding in the immature rat uterine cytosol receptor assay, with relative binding affinities of 0.1-3.6% of estradiol. None of the new compounds were estrogenic in the 3-day immature mouse uterotrophic assay at doses up to 750 micrograms. In the 3-day immature mouse antiuterotrophic assay, five DTACs with either a methoxy (5a), benzyloxy (4d, 5c), or (dimethylamino)ethoxy (7a, 7b) central ring side chain produced significant decreases in uterine weight at doses up to 750 micrograms. One compound, (Z)-1,1-dichloro-2-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- methoxyphenyl)-3-phenylcyclopropane (7b), elicited a dose-dependent decrease in vivo comparable to MER 25. These same five compounds, as well as the lead compound Analog II, were active in vitro against the estrogen-dependent MCF-7 human breast tumor cell line in a dose-dependent fashion.
|
Antiproliferative activity against estrogen receptor positive MCF-7 human breast cancer cell line at 10e-9 M. (p<0.05)
|
Homo sapiens
|
20.5
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes as pure antiestrogens.
Year : 1991
Volume : 34
Issue : 2
First Page : 842
Last Page : 851
Authors : Day BW, Magarian RA, Jain PT, Pento JT, Mousissian GK, Meyer KL.
Abstract : A series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs) was synthesized and evaluated as pure antiestrogens. Addition of 4-methoxy- or 4-(benzyloxy)phenyl Grignard reagents to p-methoxy, p-benzyloxy, or unsubstituted deoxybenzoins, followed by dehydration of the resulting carbinols produced a mixture of E and Z olefins, which were reacted with dichlorocarbene to give O-protected DTACs. The E and Z isomers were separated by fractional crystallization and the central or geminal phenyl ring was deprotected to provide phenolic DTACs. Alkylation with (N,N-dimethylamino)ethyl chloride yielded basic cyclopropanes. Two chlorodiarylindenes were isolated as thermolysis products of the DTACs, and one was converted to a phenol by hydrogenolysis. All DTACs and indenes were competitive inhibitors of [3H]estradiol binding in the immature rat uterine cytosol receptor assay, with relative binding affinities of 0.1-3.6% of estradiol. None of the new compounds were estrogenic in the 3-day immature mouse uterotrophic assay at doses up to 750 micrograms. In the 3-day immature mouse antiuterotrophic assay, five DTACs with either a methoxy (5a), benzyloxy (4d, 5c), or (dimethylamino)ethoxy (7a, 7b) central ring side chain produced significant decreases in uterine weight at doses up to 750 micrograms. One compound, (Z)-1,1-dichloro-2-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- methoxyphenyl)-3-phenylcyclopropane (7b), elicited a dose-dependent decrease in vivo comparable to MER 25. These same five compounds, as well as the lead compound Analog II, were active in vitro against the estrogen-dependent MCF-7 human breast tumor cell line in a dose-dependent fashion.
|
Binding affinity for estrogen receptor
|
Homo sapiens
|
157.0
nM
|
|
Journal : J. Med. Chem.
Title : Flexible estrogen receptor modulators: design, synthesis, and antagonistic effects in human MCF-7 breast cancer cells.
Year : 2001
Volume : 44
Issue : 7
First Page : 1072
Last Page : 1084
Authors : Meegan MJ, Hughes RB, Lloyd DG, Williams DC, Zisterer DM.
Abstract : Although many series of estrogen receptor antagonists continue to be produced, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and their antiproliferative effects on human MCF-7 breast tumor cells investigated. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introduction of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxifen standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high binding affinity. A computational study was undertaken to investigate the compounds' potential interactions with specific residues within the human estrogen receptor alpha ligand-binding domain (ER-LBD), predicting these compounds bind in an antiestrogenic fashion within the ER-LBD and interact with those important residues previously identified in the structures of ER-LBD agonist/antagonist cocrystals. These compounds further illustrate the eclectic nature of the estrogen receptor in terms of ligand flexibility tolerance.
|
Inhibition of estradiol binding to estrogen receptor in Human Breast cancer cytosol (3.3% ethanol)
|
Homo sapiens
|
11.9
nM
|
|
Journal : J. Med. Chem.
Title : (S)-(+)-4-[7-(2,2-dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl 2,2-dimethylpropanoate (EM-800): a highly potent, specific, and orally active nonsteroidal antiestrogen.
Year : 1997
Volume : 40
Issue : 14
First Page : 2117
Last Page : 2122
Authors : Gauthier S, Caron B, Cloutier J, Dory YL, Favre A, Larouche D, Mailhot J, Ouellet C, Schwerdtfeger A, Leblanc G, Martel C, Simard J, Mérand Y, Bélanger A, Labrie C, Labrie F.
|
Apparent inhibition constant for estrogen receptor in Human uterine cytosol in 3.3%ethanol
|
Homo sapiens
|
34.4
nM
|
|
Journal : J. Med. Chem.
Title : (S)-(+)-4-[7-(2,2-dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl 2,2-dimethylpropanoate (EM-800): a highly potent, specific, and orally active nonsteroidal antiestrogen.
Year : 1997
Volume : 40
Issue : 14
First Page : 2117
Last Page : 2122
Authors : Gauthier S, Caron B, Cloutier J, Dory YL, Favre A, Larouche D, Mailhot J, Ouellet C, Schwerdtfeger A, Leblanc G, Martel C, Simard J, Mérand Y, Bélanger A, Labrie C, Labrie F.
|
Inhibitory concentration against estrogen receptor alpha using estrogen response element (ERE) assay.
|
None
|
622.0
nM
|
|
Journal : J. Med. Chem.
Title : Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2003
Volume : 46
Issue : 14
First Page : 2945
Last Page : 2957
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Halleux C, Kallen J, Keller H, Schlaeppi JM, Stark W.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.
|
Displacement of [3H]17-beta-estradiol from human estrogen receptor alpha
|
Homo sapiens
|
42.0
nM
|
|
Journal : J. Med. Chem.
Title : Carboxylic acid analogues of tamoxifen: (Z)-2-[p-(1, 2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine. Estrogen receptor affinity and estrogen antagonist effects in MCF-7 cells.
Year : 1999
Volume : 42
Issue : 16
First Page : 3126
Last Page : 3133
Authors : Kraft KS, Ruenitz PC, Bartlett MG.
Abstract : The triarylethylene estrogen mimetic (E, Z)-4-[1-(p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxyacetic acid (4) represents a novel class of estrogen receptor (ER) ligands which, like tamoxifen (1), can elicit estrogen agonist and antagonist effects, in turn, in nonreproductive and reproductive tissues. Analogues of 4, incorporating structural features shown previously in triarylethylenes to improve ER affinity and estrogen antagonist properties, were prepared with the ultimate aim of identifying substances with improved estrogenicity exclusive of reproductive tissues. Thus, the side chain of 4 was elongated to give oxybutyric acid 13, which was further altered by (a) repositioning of its p-hydroxyl to the neighboring m-position (12) and (b) ethylenic bond reduction (14). Also, the p-hydroxyl group and oxyacetic acid groups of 4 were, in turn, shifted to the neighboring m-positions, affording 8 and 9. Oxybutyric acid analogue 13 had about 2 times the affinity for human ERalpha as 4, and its antiproliferative effect in MCF-7 cells was greater than that of 1. Dihydro analogue 14, which was conformationally similar to cis-13, had very low ER affinity and antiestrogenicity, and m-hydroxy analogue 12 also had reduced ER affinity and potency, but its MCF-7 cell antiproliferative efficacy was retained. Modest ER affinity and antiproliferative potency were seen with 8, in which phenolic and phenyl rings were trans to one another, but 9, in which these rings were cis, was inactive. Our findings indicate that two-carbon side-chain elongation and/or m-positioning of the hydroxyl group in 4 affords analogues with dominant estrogen antagonist effects in MCF-7 cells.
|
Displacement of radioligand from Estrogen receptor alpha
|
None
|
8.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a novel fluorescent probe for estrogen receptor.
Year : 2002
Volume : 12
Issue : 9
First Page : 1283
Last Page : 1285
Authors : Adamczyk M, Reddy RE, Yu Z.
Abstract : A novel estradiol-mimetic fluorescent probe 5 was synthesized from diethylstilbestrol (DES, 1), which is useful for probing estrogen receptor (ERalpha), a prognostic indicator of estrogen-dependent cancers, and for developing a homogeneous fluorescence polarization (FP) assay to identify the ligands of estrogen receptor.
|
Concentration of compound required to induce 50 % of the maximum stimulation of alkaline phosphatase activity in Ishikawa cells
|
Homo sapiens
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-[4-(1,2-Diphenylbut-1-enyl)phenyl]acrylic acid: a non-steroidal estrogen with functional selectivity for bone over uterus in rats.
Year : 1994
Volume : 37
Issue : 11
First Page : 1550
Last Page : 1552
Authors : Willson TM, Henke BR, Momtahen TM, Charifson PS, Batchelor KW, Lubahn DB, Moore LB, Oliver BB, Sauls HR, Triantafillou JA.
|
Inhibition of estrogen receptor positive MCF-7 human breast cancer cell proliferation
|
Homo sapiens
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of tubulin polymerization by 5,6-dihydroindolo[2,1-alpha]isoquinoline derivatives.
Year : 1997
Volume : 40
Issue : 22
First Page : 3524
Last Page : 3533
Authors : Goldbrunner M, Loidl G, Polossek T, Mannschreck A, von Angerer E.
Abstract : 6-Alkyl-12-formyl-5,6-dihydroindolo[2,1-alpha]isoquinolines have been shown to inhibit the growth of human mammary carcinoma cells by an unknown mode of action. One of the possible molecular targets is the tubulin system which is involved in cell division. A number of 5,6-dihydroindolo[2,1-alpha]isoquinolines with methoxy or hydroxy groups in positions 3, 9, and/or 10 and various functional groups such as formyl, acetyl, cyano, alkylimino, and alkylamino in position 12 were synthesized and evaluated for both inhibition of tubulin polymerization and cytostatic activity in MDA-MB 231 and MCF-7 human breast cancer cells. In the tubulin polymerization assay, only hydroxy derivatives were active, whereas both the hydroxy derivatives and some of the methoxy compounds inhibited cell growth. In order to establish a correlation between the inhibition of tubulin polymerization and cytostatic activity in the hydroxy series, two of the most active racemates were separated into the enantiomers. In both assays, the relative potencies of the hydroxy derivatives were in a similar order. Highest activity was found for the (+)-isomers of 6-propyl- (6b) and 6-butyl-12-formyl-5,6-hydro-3,9-dihydroxyindolo[2,1-alpha]isoquino line (6c) with IC50 values of 11 +/- 0.4 and 3.1 +/- 0.4 microM, respectively, for the polymerization of tubulin at 37 degrees C (colchicine: 2.1 +/- 0.1 microM). The active hydroxy derivatives displaced 40-70% of [3H]colchicine from its binding site in the tubulin at concentrations 10-fold higher than that of colchicine. The data suggest that hydroxy-substituted indolo[2,1-alpha]isoquinolines bind to the colchicine-binding site and inhibit the polymerization of tubulin. This action can be assumed to be responsible for the cytostatic activity of the hydroxy derivatives and might also contribute to the antitumor effect of the corresponding methyl ethers.
|
Inhibition of estrogen receptor positive MCF-7 breast cancer cell proliferation
|
Homo sapiens
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of doxorubicin-formaldehyde conjugates targeted to breast cancer cells.
Year : 2004
Volume : 47
Issue : 5
First Page : 1193
Last Page : 1206
Authors : Burke PJ, Koch TH.
Abstract : The anthracycline antitumor drug doxorubicin (DOX) has been utilized for decades as a broad-spectrum chemotherapeutic. Recent literature evidence documents the role of formaldehyde in the cytotoxic mechanism, and anthracycline-formaldehyde conjugates possess substantially enhanced activity in vitro and in vivo. Targeting a doxorubicin-formaldehyde conjugate specifically to cancer cells may provide a more efficacious chemotherapeutic. The design and 11-step synthesis of doxorubicin-formaldehyde conjugates targeted to the estrogen receptor, which is commonly overexpressed in breast cancer cells, are reported. The formaldehyde is incorporated in a masked form as an N-Mannich linkage between doxorubicin and salicylamide. The salicylamide triggering molecule, previously developed to release the doxorubicin-formaldehyde active metabolite, is tethered via derivatized ethylene glycols to an E and Z mixture of 4-hydroxytamoxifen. The targeting group, E/Z-4-hydroxytamoxifen, was selected for its ability to tightly bind the estrogen receptor and antiestrogen binding sites. The targeted doxorubicin-formaldehyde conjugates' estrogen receptor binding and in vitro growth inhibition were evaluated as a function of tether length. The lead compound, DOX-TEG-TAM, bearing a triethylene glycol tether, binds the estrogen receptor with a binding affinity of 2.5% relative to E/Z-4-hydroxytamoxifen and inhibits the growth of four breast cancer cell lines with 4-fold up to 140-fold enhanced activity relative to doxorubicin.
|
Percent inhibition of estrogen receptor positive MCF-7 human breast cancer cell proliferation at 10e-7 M
|
Homo sapiens
|
52.0
%
|
|
Journal : J. Med. Chem.
Title : Molecular structures and conformational studies of triarylcyclopropyl and related nonsteroidal antiestrogens.
Year : 1994
Volume : 37
Issue : 11
First Page : 1670
Last Page : 1683
Authors : Hossain MB, van der Helm D, Schmitz FJ, Pordesimo EO, Magarian RA, Meyer KL, Overacre LB, Day BW.
Abstract : Molecular structures and conformational characteristics of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs), which were reported previously to be distinctly antiestrogenic and inhibitors of the estrogen-receptor-positive MCF-7 human breast cancer cells in culture, are reported. In addition, structural and conformational features of the DTACs were compared to the first-known nonsteroidal antiestrogen, MER25, and the clinically useful antiestrogen Tamoxifen. The molecular structures of four DTAC compounds were determined by X-ray diffraction. Crystallographic structures show that the DTAC molecules have nearly the same relative conformation for the three aryl rings which is designated as a "nonpropeller" conformation in contrast to the observed "propeller" conformation for the three rings in all known triarylethylenes. Systematic conformational searches were performed to find the conformational preferences of DTACs, MER25, and Tamoxifen using idealized model compounds built from their respective crystal structure. Energy-minimization and conformational-search studies demonstrated that all DTAC molecules have a common, single global minimum energy conformer for their central core containing the dichlorotriarylcyclopropyl system, which is similar to that found in their crystal structures. Conformational search of MER25 showed that the molecule can assume a number of low-energy conformers of which two, one anti (A1) and one gauche (G1A), have about the same energy. The anti conformation is similar to the one observed in its crystal structure and resembles the estrogenic E-isomer of Tamoxifen, while the lowest energy gauche conformer of MER25 resembles more closely the antiestrogenic Z-isomer of Tamoxifen. NMR spectroscopic analysis of MER25 showed that the molecule exists predominantly in the anti conformation in solution. A comparative review of the structural features and bioactivities of Tamoxifen, DTACs, and MER25 provides a possible explanation for their low estrogen receptor binding affinity which is common to these compounds together with their antiestrogenic activity.
|
Inhibition of estrogen receptor negative MDA-MB-231 breast cancer cell proliferation
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of doxorubicin-formaldehyde conjugates targeted to breast cancer cells.
Year : 2004
Volume : 47
Issue : 5
First Page : 1193
Last Page : 1206
Authors : Burke PJ, Koch TH.
Abstract : The anthracycline antitumor drug doxorubicin (DOX) has been utilized for decades as a broad-spectrum chemotherapeutic. Recent literature evidence documents the role of formaldehyde in the cytotoxic mechanism, and anthracycline-formaldehyde conjugates possess substantially enhanced activity in vitro and in vivo. Targeting a doxorubicin-formaldehyde conjugate specifically to cancer cells may provide a more efficacious chemotherapeutic. The design and 11-step synthesis of doxorubicin-formaldehyde conjugates targeted to the estrogen receptor, which is commonly overexpressed in breast cancer cells, are reported. The formaldehyde is incorporated in a masked form as an N-Mannich linkage between doxorubicin and salicylamide. The salicylamide triggering molecule, previously developed to release the doxorubicin-formaldehyde active metabolite, is tethered via derivatized ethylene glycols to an E and Z mixture of 4-hydroxytamoxifen. The targeting group, E/Z-4-hydroxytamoxifen, was selected for its ability to tightly bind the estrogen receptor and antiestrogen binding sites. The targeted doxorubicin-formaldehyde conjugates' estrogen receptor binding and in vitro growth inhibition were evaluated as a function of tether length. The lead compound, DOX-TEG-TAM, bearing a triethylene glycol tether, binds the estrogen receptor with a binding affinity of 2.5% relative to E/Z-4-hydroxytamoxifen and inhibits the growth of four breast cancer cell lines with 4-fold up to 140-fold enhanced activity relative to doxorubicin.
|
Effective dose for [3H]- estradiol against proliferation of MCF-7 cells
|
Homo sapiens
|
0.11
nM
|
|
Journal : J. Med. Chem.
Title : Effect of triphenylacrylonitrile derivatives on estradiol-receptor binding and on human breast cancer cell growth.
Year : 1989
Volume : 32
Issue : 9
First Page : 2092
Last Page : 2103
Authors : Bignon E, Pons M, Crastes de Paulet AC, Doré JC, Gilbert J, Abecassis J, Miquel JF, Ojasoo T, Raynaud JP.
Abstract : In a study of a series of 26 triphenylacrylonitrile derivatives (TPEs), we investigated the influence of several possibly interrelated factors on the proliferation of human breast cancer cell lines. (1) Chemical substituents: the test compounds were for the most part para-hydroxylated with increasingly bulky hydrophobic and/or basic side chains [isopropyloxy or (diethylamino)ethoxy] or standard reference compounds. (2) Relative binding affinities (RBAs): they competed diversely for [3H]estradiol (E2) binding to calf uterus cytosol and little, if at all, for binding to the [3H]tamoxifen-labeled antiestrogen binding site (AEBS) in lower speed supernatant. A multiparametric comparison of RBAs recorded for calf, rat, and mouse uterus cytosol estrogen receptor (ER) revealed a possible influence of species-specific receptor conformation and/or environment on binding. (3) Estrogen/antiestrogen potency: their stimulation and inhibition of the proliferation of the ER-positive human breast cancer cell line (MCF7) was measured. Compounds with only hydroxy substituents stimulated proliferation more markedly than methylated derivatives and had a maximum effect at 10(-11)-10(-6) M. Stimulation was related to the RBA for ER. Compounds with isopropyloxy or (diethylamino)ethoxy side chains only weakly stimulated MCF7 cell growth and more powerfully antagonized E2-promoted growth. The extent of inhibition depended upon the bulk of the side chain and could be reversed by 10(-7) M E2. Within the same concentration ranges, the test compounds were without effect on the BT20 ER-negative cell line. (4) Cytostatic and/or cytolytic activity: most compounds could arrest the proliferation of both MCF7 and BT20 cells at concentrations above 3 x 10(-6) M. This activity was thus independent of ER. Nevertheless, those compounds with a charged hydrophobic side chain, which were the most powerful antagonists of E2-promoted cell growth, were also the most cytotoxic. The overall results for all molecules on all parameters were submitted to a multivariate analysis (correspondence analysis) which revealed the progressive influence of increasing substitution by hydroxy and more bulky groups on the generation of antagonist activity and cytotoxicity.
|
Antagonist effect in breast tissue was assayed by inhibition of estrogen stimulated MCF-7 cell proliferation
|
None
|
530.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Versatile raloxifene triflates
Year : 1997
Volume : 7
Issue : 7
First Page : 887
Last Page : 892
Authors : Martin MJ, Grese TA, Glasebrook AL, Matsumoto K, Pennington LD, Phillips D, Short LL
|
In vitro inhibition of MCF-7 cell proliferation compared to 0.1 nM [3H]-estradiol.
|
Homo sapiens
|
219.0
nM
|
|
Journal : J. Med. Chem.
Title : Effect of triphenylacrylonitrile derivatives on estradiol-receptor binding and on human breast cancer cell growth.
Year : 1989
Volume : 32
Issue : 9
First Page : 2092
Last Page : 2103
Authors : Bignon E, Pons M, Crastes de Paulet AC, Doré JC, Gilbert J, Abecassis J, Miquel JF, Ojasoo T, Raynaud JP.
Abstract : In a study of a series of 26 triphenylacrylonitrile derivatives (TPEs), we investigated the influence of several possibly interrelated factors on the proliferation of human breast cancer cell lines. (1) Chemical substituents: the test compounds were for the most part para-hydroxylated with increasingly bulky hydrophobic and/or basic side chains [isopropyloxy or (diethylamino)ethoxy] or standard reference compounds. (2) Relative binding affinities (RBAs): they competed diversely for [3H]estradiol (E2) binding to calf uterus cytosol and little, if at all, for binding to the [3H]tamoxifen-labeled antiestrogen binding site (AEBS) in lower speed supernatant. A multiparametric comparison of RBAs recorded for calf, rat, and mouse uterus cytosol estrogen receptor (ER) revealed a possible influence of species-specific receptor conformation and/or environment on binding. (3) Estrogen/antiestrogen potency: their stimulation and inhibition of the proliferation of the ER-positive human breast cancer cell line (MCF7) was measured. Compounds with only hydroxy substituents stimulated proliferation more markedly than methylated derivatives and had a maximum effect at 10(-11)-10(-6) M. Stimulation was related to the RBA for ER. Compounds with isopropyloxy or (diethylamino)ethoxy side chains only weakly stimulated MCF7 cell growth and more powerfully antagonized E2-promoted growth. The extent of inhibition depended upon the bulk of the side chain and could be reversed by 10(-7) M E2. Within the same concentration ranges, the test compounds were without effect on the BT20 ER-negative cell line. (4) Cytostatic and/or cytolytic activity: most compounds could arrest the proliferation of both MCF7 and BT20 cells at concentrations above 3 x 10(-6) M. This activity was thus independent of ER. Nevertheless, those compounds with a charged hydrophobic side chain, which were the most powerful antagonists of E2-promoted cell growth, were also the most cytotoxic. The overall results for all molecules on all parameters were submitted to a multivariate analysis (correspondence analysis) which revealed the progressive influence of increasing substitution by hydroxy and more bulky groups on the generation of antagonist activity and cytotoxicity.
|
Percent of inhibitory activity against proliferation of MCF-7 cells in presence of 10e-6 M concentration of [3H]estradiol (E2).
|
Homo sapiens
|
49.0
%
|
|
Journal : J. Med. Chem.
Title : Effect of triphenylacrylonitrile derivatives on estradiol-receptor binding and on human breast cancer cell growth.
Year : 1989
Volume : 32
Issue : 9
First Page : 2092
Last Page : 2103
Authors : Bignon E, Pons M, Crastes de Paulet AC, Doré JC, Gilbert J, Abecassis J, Miquel JF, Ojasoo T, Raynaud JP.
Abstract : In a study of a series of 26 triphenylacrylonitrile derivatives (TPEs), we investigated the influence of several possibly interrelated factors on the proliferation of human breast cancer cell lines. (1) Chemical substituents: the test compounds were for the most part para-hydroxylated with increasingly bulky hydrophobic and/or basic side chains [isopropyloxy or (diethylamino)ethoxy] or standard reference compounds. (2) Relative binding affinities (RBAs): they competed diversely for [3H]estradiol (E2) binding to calf uterus cytosol and little, if at all, for binding to the [3H]tamoxifen-labeled antiestrogen binding site (AEBS) in lower speed supernatant. A multiparametric comparison of RBAs recorded for calf, rat, and mouse uterus cytosol estrogen receptor (ER) revealed a possible influence of species-specific receptor conformation and/or environment on binding. (3) Estrogen/antiestrogen potency: their stimulation and inhibition of the proliferation of the ER-positive human breast cancer cell line (MCF7) was measured. Compounds with only hydroxy substituents stimulated proliferation more markedly than methylated derivatives and had a maximum effect at 10(-11)-10(-6) M. Stimulation was related to the RBA for ER. Compounds with isopropyloxy or (diethylamino)ethoxy side chains only weakly stimulated MCF7 cell growth and more powerfully antagonized E2-promoted growth. The extent of inhibition depended upon the bulk of the side chain and could be reversed by 10(-7) M E2. Within the same concentration ranges, the test compounds were without effect on the BT20 ER-negative cell line. (4) Cytostatic and/or cytolytic activity: most compounds could arrest the proliferation of both MCF7 and BT20 cells at concentrations above 3 x 10(-6) M. This activity was thus independent of ER. Nevertheless, those compounds with a charged hydrophobic side chain, which were the most powerful antagonists of E2-promoted cell growth, were also the most cytotoxic. The overall results for all molecules on all parameters were submitted to a multivariate analysis (correspondence analysis) which revealed the progressive influence of increasing substitution by hydroxy and more bulky groups on the generation of antagonist activity and cytotoxicity.
|
Percent of inhibitory activity versus 0.1 nm [3H]estradiol against proliferation of MCF-7 cells.
|
Homo sapiens
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Effect of triphenylacrylonitrile derivatives on estradiol-receptor binding and on human breast cancer cell growth.
Year : 1989
Volume : 32
Issue : 9
First Page : 2092
Last Page : 2103
Authors : Bignon E, Pons M, Crastes de Paulet AC, Doré JC, Gilbert J, Abecassis J, Miquel JF, Ojasoo T, Raynaud JP.
Abstract : In a study of a series of 26 triphenylacrylonitrile derivatives (TPEs), we investigated the influence of several possibly interrelated factors on the proliferation of human breast cancer cell lines. (1) Chemical substituents: the test compounds were for the most part para-hydroxylated with increasingly bulky hydrophobic and/or basic side chains [isopropyloxy or (diethylamino)ethoxy] or standard reference compounds. (2) Relative binding affinities (RBAs): they competed diversely for [3H]estradiol (E2) binding to calf uterus cytosol and little, if at all, for binding to the [3H]tamoxifen-labeled antiestrogen binding site (AEBS) in lower speed supernatant. A multiparametric comparison of RBAs recorded for calf, rat, and mouse uterus cytosol estrogen receptor (ER) revealed a possible influence of species-specific receptor conformation and/or environment on binding. (3) Estrogen/antiestrogen potency: their stimulation and inhibition of the proliferation of the ER-positive human breast cancer cell line (MCF7) was measured. Compounds with only hydroxy substituents stimulated proliferation more markedly than methylated derivatives and had a maximum effect at 10(-11)-10(-6) M. Stimulation was related to the RBA for ER. Compounds with isopropyloxy or (diethylamino)ethoxy side chains only weakly stimulated MCF7 cell growth and more powerfully antagonized E2-promoted growth. The extent of inhibition depended upon the bulk of the side chain and could be reversed by 10(-7) M E2. Within the same concentration ranges, the test compounds were without effect on the BT20 ER-negative cell line. (4) Cytostatic and/or cytolytic activity: most compounds could arrest the proliferation of both MCF7 and BT20 cells at concentrations above 3 x 10(-6) M. This activity was thus independent of ER. Nevertheless, those compounds with a charged hydrophobic side chain, which were the most powerful antagonists of E2-promoted cell growth, were also the most cytotoxic. The overall results for all molecules on all parameters were submitted to a multivariate analysis (correspondence analysis) which revealed the progressive influence of increasing substitution by hydroxy and more bulky groups on the generation of antagonist activity and cytotoxicity.
|
Inhibition of estradiol induced estrogen receptor transcriptional activation in MCF-7-2a cells
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Antiestrogenically active 1,1,2-tris(4-hydroxyphenyl)alkenes without basic side chain: synthesis and biological activity.
Year : 2003
Volume : 46
Issue : 8
First Page : 1484
Last Page : 1491
Authors : Lubczyk V, Bachmann H, Gust R.
Abstract : C2-Alkyl substituted derivatives of the 1,1,2-tris(4-hydroxyphenyl)ethene 3a (alkyl = Me (3b), Et (3c), Prop (3d), But (3e)) were synthesized by reaction of 1,2-bis(4-methoxyphenyl)ethanone with the appropriate alkyl halide, followed by a Grignard reaction with 4-methoxyphenylmagnesium bromide, dehydration with phosphoric acid or hydrobromic acid, and ether cleavage with BBr(3). The compounds were tested for estrogen receptor (ER) binding affinity in a competition experiment with radio labeled estradiol ([(3)H]-E2) and for gene activation on the ER-positive MCF-7-2a cell line. All compounds showed high receptor binding affinity (RBA-value: 3b (52.1%) > 3a (45.5%) > 3c (29.6%) > 3d (4.03%) > 3e (0.95%)). The tests on hormone dependent MCF-7-2a breast cancer cells, stably transfected with the plasmid ERE(wtc)luc, revealed that all 1,1,2-tris(4-hydroxyphenyl)ethenes antagonized the effect of 1 nM estradiol (E2). The compounds 3b (IC(50) = 15 nM) and 3c (IC(50) = 10 nM) were equal in their effects to 4-hydroxytamoxifen (4OHT) (IC(50) = 7 nM). Agonistic effects were low. Only 3a and 3b activated the luciferase expression (relative activation at 1 microM: 3a 60%; 3b 35%). Despite their highly antagonistic potency, the 1,1,2-tris(4-hydroxyphenyl)ethenes showed only low cytotoxic properties on the hormone sensitive MCF-7 cell line.
|
Inhibition of estrogen-induced proliferation in human MCF-7 breast cancer cells
|
Homo sapiens
|
481.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and synthesis of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]b enzo[b]thiophene: a novel, highly potent, selective estrogen receptor modulator.
Year : 1997
Volume : 40
Issue : 10
First Page : 1407
Last Page : 1416
Authors : Palkowitz AD, Glasebrook AL, Thrasher KJ, Hauser KL, Short LL, Phillips DL, Muehl BS, Sato M, Shetler PK, Cullinan GJ, Pell TR, Bryant HU.
Abstract : Raloxifene,[2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (2), is representative of a class of compounds known as selective estrogen receptor modulators (SERMs) that possess estrogen agonist-like actions on bone tissues and serum lipids while displaying potent estrogen antagonist properties in the breast and uterus. As part of ongoing SAR studies with raloxifene, we found that replacement of the carbonyl group with oxygen ([6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]b enzo[b]thiophene hydrochloride, 4c) resulted in a substantial (10-fold) increase in estrogen antagonist potency relative to raloxifene in an in vitro estrogen dependent cell proliferation assay (IC50 = 0.05 nM) in which human breast cancer cells (MCF-7) were utilized. In vivo, 4c potently inhibited the uterine proliferative response to exogenous estrogen in immature rats following both sc and oral dosing (ED50 of 0.006 and 0.25 mg/kg, respectively). In ovariectomized aged rats, 4c produced a significant maximal decrease (45%) in total cholesterol at 1.0 mg/kg (p.o.) and showed a protective effect on bone relative to controls with maximal efficacy at 1.0 mg/kg (p.o.). These data identify 4c as a novel SERM with greater potency to antagonize estrogen in uterine tissue and in human mammary cancer cells compared to raloxifene, tamoxifen or ICI-182,780.
|
Effective concentration against MCF-7 breast tumor cells using MCF-7 assay.
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2003
Volume : 46
Issue : 14
First Page : 2945
Last Page : 2957
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Halleux C, Kallen J, Keller H, Schlaeppi JM, Stark W.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.
|
Inhibitory concentration against MCF-7 breast tumor cells using MCF-7 assay.
|
Homo sapiens
|
580.0
nM
|
|
Journal : J. Med. Chem.
Title : Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2003
Volume : 46
Issue : 14
First Page : 2945
Last Page : 2957
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Halleux C, Kallen J, Keller H, Schlaeppi JM, Stark W.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.
|
Cytostatic activity against MCF-7 cell proliferation.
|
Homo sapiens
|
49.0
%
|
|
Journal : J. Med. Chem.
Title : Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation.
Year : 1992
Volume : 35
Issue : 3
First Page : 573
Last Page : 583
Authors : Doré JC, Gilbert J, Bignon E, Crastes de Paulet A, Ojasoo T, Pons M, Raynaud JP, Miquel JF.
Abstract : The response profiles of 36 para-substituted diphenylethylenes (DPEs) and triphenylacrylonitriles (TPEs) have been compared by multivariate analysis. The responses measured were (a) relative binding affinity (RBA) for the cytosol estrogen receptor (ER), (b) ability to promote the growth of the human MCF7 breast cancer cell-line, (c) cytotoxicity in MCF7 cells, and (d) ability to stimulate or inhibit protein kinase C (PKC) III activity under three different conditions of enzyme activation. The prime object of the analysis was to observe the simultaneous influence of diverse combinations of substituents on all these in vitro responses. To do this, the minimum spanning tree (MST) method was used to organize the molecules into a network in which proximate molecules are closely related with regard to their responses whereas remote molecules are distinct. The MST of this population of molecules had four main branches. E2 and its TPE mime were located in a central position within the trunk whereas the tips of the branches tended toward molecules of different specificity, i.e., cytotoxic molecules that bind to ER and interfere with PKC, noncytotoxic molecules that also bind to ER and interfere with PKC but promote cell growth, molecules only active on PKC, and molecules active on all parameters except PKC stimulation. A parallel MST analysis of the relationships among the response parameters themselves confirmed previous conclusions: For this population of molecules, RBAs for ER are fairly closely related to ability to promote MCF7 cell growth and only little to cytotoxicity (Bignon et al. J. Med. Chem. 1989, 32, 2092). Cytotoxicity is much more clearly correlated with inhibition of diacylglycerol-stimulated PKC activity than with RBAs for ER. PKC inhibition differs substantially depending upon whether the substrate is H1 histone or protamine sulfate.
|
Anti-proliferative activity against estrogen-responsive human breast cancer cell line MCF-7 in the presence of ER at a 10e-4 uM concentration of estradiol
|
Homo sapiens
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer.
Year : 1996
Volume : 39
Issue : 18
First Page : 3461
Last Page : 3469
Authors : Akama T, Shida Y, Sugaya T, Ishida H, Gomi K, Kasai M.
Abstract : In the course of our search for new antitumor agents in breast cancer, novel amino-substituted flavone derivatives were synthesized and examined for antitumor activities. Among them, 5,4'-diaminoflavone and some of its congeners showed remarkable antiproliferative activity against the estrogen receptor (ER)-positive and estrogen-responsive human breast cancer cell line MCF-7. The activity was observed irrespective of the presence or absence of estrogen. The 5-aminoflavone derivatives (5-AFs) are not classical anti-estrogens because they did not compete with [3H]estradiol to bind the estrogen receptor. Moreover, 5-AFs showed antitumor activity highly selective to the ER-positive breast cancer cell line, and they showed no effects against the ER-negative human cancer cell lines HeLa S3, WiDr, and MDA-MB-453. Although the mechanism of their selective antitumor activity to ER-positive breast cancer cells is unclear, 5-AFs are expected to be a new type of antitumor agents in breast cancer.
|
Inhibition of 17-beta-estradiol (10e-11 M) mediated MCF-7 cell proliferation
|
Homo sapiens
|
904.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of trans-2,3-dihydroraloxifene.
Year : 1999
Volume : 9
Issue : 8
First Page : 1137
Last Page : 1140
Authors : Schmid CR, Glasebrook AL, Misner JW, Stephenson GA.
Abstract : The synthesis and biological evaluation of trans-2,3-dihydroraloxifene, 2, is described. The synthesis proceeds in 8 steps in 20% overall yield. Relative trans 2,3-stereochemistry is definitively established in ester 6, which is converted to the title compound via derivatization, Grignard addition, and deprotection. Evaluation in vitro shows the compound to be a potent selective estrogen receptor modulator (SERM).
|
Inhibition of MDA-MB-435 breast cancer cell proliferation
|
Homo sapiens
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of doxorubicin-formaldehyde conjugates targeted to breast cancer cells.
Year : 2004
Volume : 47
Issue : 5
First Page : 1193
Last Page : 1206
Authors : Burke PJ, Koch TH.
Abstract : The anthracycline antitumor drug doxorubicin (DOX) has been utilized for decades as a broad-spectrum chemotherapeutic. Recent literature evidence documents the role of formaldehyde in the cytotoxic mechanism, and anthracycline-formaldehyde conjugates possess substantially enhanced activity in vitro and in vivo. Targeting a doxorubicin-formaldehyde conjugate specifically to cancer cells may provide a more efficacious chemotherapeutic. The design and 11-step synthesis of doxorubicin-formaldehyde conjugates targeted to the estrogen receptor, which is commonly overexpressed in breast cancer cells, are reported. The formaldehyde is incorporated in a masked form as an N-Mannich linkage between doxorubicin and salicylamide. The salicylamide triggering molecule, previously developed to release the doxorubicin-formaldehyde active metabolite, is tethered via derivatized ethylene glycols to an E and Z mixture of 4-hydroxytamoxifen. The targeting group, E/Z-4-hydroxytamoxifen, was selected for its ability to tightly bind the estrogen receptor and antiestrogen binding sites. The targeted doxorubicin-formaldehyde conjugates' estrogen receptor binding and in vitro growth inhibition were evaluated as a function of tether length. The lead compound, DOX-TEG-TAM, bearing a triethylene glycol tether, binds the estrogen receptor with a binding affinity of 2.5% relative to E/Z-4-hydroxytamoxifen and inhibits the growth of four breast cancer cell lines with 4-fold up to 140-fold enhanced activity relative to doxorubicin.
|
Anti-estrogenicity for 50% inhibition of the MVLN cell luciferase activity due to 0.1 nM E2 (estradiol)
|
Homo sapiens
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Cytotoxicity and antiestrogenicity of a novel series of basic diphenylethylenes.
Year : 1997
Volume : 40
Issue : 7
First Page : 1104
Last Page : 1111
Authors : Gilbert J, Fuentes M, Ojasoo T, Doré JC, Pons M.
Abstract : On the premise that it is necessary to develop antiestrogens with a higher cytotoxic component in order to reduce the risks of the development of heterogeneous malignant cell populations in breast cancer, we studied a novel series of basic diphenylethylenes, for the most part devoid of estrogenic activity, with low antiestrogenicity but much enhanced cytotoxicity compared to the reference drug tamoxifen. The main structural features associated with cytotoxicity were E isomery, substituents of five to eight carbons on the ethylene bond, and dibasicity.
|
Inhibition of estradiol-induced uterine weight gain in ovariectomized BALB/c mice at 20 ug dose twice daily
|
Mus musculus
|
3.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of new halo-steroidal antiestrogens.
Year : 1991
Volume : 34
Issue : 5
First Page : 1624
Last Page : 1630
Authors : Levesque C, Merand Y, Dufour JM, Labrie C, Labrie F.
Abstract : Antiestrogen therapy is the most widely used endocrine manipulation for the treatment of breast cancer, especially in postmenopausal women. Unfortunately, the compounds presently available possess mixed agonistic/antagonistic activity, thus potentially limiting their therapeutic efficacy. Following the observations that an aliphatic chain at the 7 alpha-position of 17 beta-estradiol does not prevent binding to the estrogen receptor while halogenation of estradiol can increase the affinity of its binding (expressed as RBA) to the estrogen receptor, we have synthesized a series of new steroidal antiestrogens (6-10) which possess both an 7 alpha-undecanamide group and an halogen atom (Cl, Br, or I) at the 16 alpha-position. The stereochemistry of these compounds was unambiguously established by high-field (400-MHz) nuclear magnetic resonance. Some of the compounds obtained possess potent in vivo antiestrogenic activity. At the low twice daily 3-micrograms dose, 16 alpha-chloro 3,17 beta-diol amide, 16 alpha-iodo 3,17 beta-diol amide, 16 alpha-bromo 3,17 beta-diol amide, 16 alpha-chloro 3,17 alpha-diol amide, and 16 alpha-bromo 3,17 alpha-diol amide inhibit by 74, 63, 52, 35, and 60%, respectively, the estradiol-induced stimulation of uterine weight in ovariectomized Balb/c mice while 78-99% blockade of estradiol action is achieved at the 20-micrograms dose. These new antiestrogens show no estrogenic activity on uterine weight at the doses used while tamoxifen (2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N- dimethylethanamine) shows full estrogenic activity and is only a weak partial antiestrogen in the same assay.
|
Inhibition of estradiol-induced uterine weight gain in ovariectomized BALB/c mice at 3 ug dose twice daily; nonsignificant
|
Mus musculus
|
7.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of new halo-steroidal antiestrogens.
Year : 1991
Volume : 34
Issue : 5
First Page : 1624
Last Page : 1630
Authors : Levesque C, Merand Y, Dufour JM, Labrie C, Labrie F.
Abstract : Antiestrogen therapy is the most widely used endocrine manipulation for the treatment of breast cancer, especially in postmenopausal women. Unfortunately, the compounds presently available possess mixed agonistic/antagonistic activity, thus potentially limiting their therapeutic efficacy. Following the observations that an aliphatic chain at the 7 alpha-position of 17 beta-estradiol does not prevent binding to the estrogen receptor while halogenation of estradiol can increase the affinity of its binding (expressed as RBA) to the estrogen receptor, we have synthesized a series of new steroidal antiestrogens (6-10) which possess both an 7 alpha-undecanamide group and an halogen atom (Cl, Br, or I) at the 16 alpha-position. The stereochemistry of these compounds was unambiguously established by high-field (400-MHz) nuclear magnetic resonance. Some of the compounds obtained possess potent in vivo antiestrogenic activity. At the low twice daily 3-micrograms dose, 16 alpha-chloro 3,17 beta-diol amide, 16 alpha-iodo 3,17 beta-diol amide, 16 alpha-bromo 3,17 beta-diol amide, 16 alpha-chloro 3,17 alpha-diol amide, and 16 alpha-bromo 3,17 alpha-diol amide inhibit by 74, 63, 52, 35, and 60%, respectively, the estradiol-induced stimulation of uterine weight in ovariectomized Balb/c mice while 78-99% blockade of estradiol action is achieved at the 20-micrograms dose. These new antiestrogens show no estrogenic activity on uterine weight at the doses used while tamoxifen (2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N- dimethylethanamine) shows full estrogenic activity and is only a weak partial antiestrogen in the same assay.
|
Antiestrogenic effect in immature mouse at a dose of 1 ug.
|
Mus musculus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Catechol estrogens of the 1,1,2-triphenylbut-1-ene type: relationship between structure, estradiol receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activities.
Year : 1986
Volume : 29
Issue : 8
First Page : 1355
Last Page : 1362
Authors : Schneider MR, Ball H, Schiller CD.
Abstract : 1,1,2-Triphenylbut-1-enes (26-35), which are substituted with one or two 3,4-diacetoxy groups or with one 3,4-diacetoxy and one 3- or 4-acetoxy group in two aromatic rings, were synthesized. The occurring E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study on structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties in the immature mouse, and inhibition of the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, most of the 1,1-disubstituted 1,1,2-triphenylbut-1-enes (29, Z-30, Z,E-31) and (E)-1-(3-acetoxyphenyl)-1-phenyl-2-(3,4-diacetoxyphenyl)but- 1-ene (E-35) as well as its respective Z isomer (Z-35) exerted antiestrogenic properties. Compounds Z-30, Z,E-31, Z-35, and E-35 inhibited the growth of the hormone-dependent MXT tumor. The best antitumor effect without estrogenic side effects during therapy was shown by E-35.
|
Antiestrogenic effect in immature mouse at a dose of 25 ug.
|
Mus musculus
|
11.0
%
|
|
Journal : J. Med. Chem.
Title : Catechol estrogens of the 1,1,2-triphenylbut-1-ene type: relationship between structure, estradiol receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activities.
Year : 1986
Volume : 29
Issue : 8
First Page : 1355
Last Page : 1362
Authors : Schneider MR, Ball H, Schiller CD.
Abstract : 1,1,2-Triphenylbut-1-enes (26-35), which are substituted with one or two 3,4-diacetoxy groups or with one 3,4-diacetoxy and one 3- or 4-acetoxy group in two aromatic rings, were synthesized. The occurring E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study on structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties in the immature mouse, and inhibition of the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, most of the 1,1-disubstituted 1,1,2-triphenylbut-1-enes (29, Z-30, Z,E-31) and (E)-1-(3-acetoxyphenyl)-1-phenyl-2-(3,4-diacetoxyphenyl)but- 1-ene (E-35) as well as its respective Z isomer (Z-35) exerted antiestrogenic properties. Compounds Z-30, Z,E-31, Z-35, and E-35 inhibited the growth of the hormone-dependent MXT tumor. The best antitumor effect without estrogenic side effects during therapy was shown by E-35.
|
In vivo anti-estrogenic effect in immature mice at 5 ug
|
Mus musculus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Catechol estrogens of the 1,1,2-triphenylbut-1-ene type: relationship between structure, estradiol receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activities.
Year : 1986
Volume : 29
Issue : 8
First Page : 1355
Last Page : 1362
Authors : Schneider MR, Ball H, Schiller CD.
Abstract : 1,1,2-Triphenylbut-1-enes (26-35), which are substituted with one or two 3,4-diacetoxy groups or with one 3,4-diacetoxy and one 3- or 4-acetoxy group in two aromatic rings, were synthesized. The occurring E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study on structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties in the immature mouse, and inhibition of the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, most of the 1,1-disubstituted 1,1,2-triphenylbut-1-enes (29, Z-30, Z,E-31) and (E)-1-(3-acetoxyphenyl)-1-phenyl-2-(3,4-diacetoxyphenyl)but- 1-ene (E-35) as well as its respective Z isomer (Z-35) exerted antiestrogenic properties. Compounds Z-30, Z,E-31, Z-35, and E-35 inhibited the growth of the hormone-dependent MXT tumor. The best antitumor effect without estrogenic side effects during therapy was shown by E-35.
|
In vitro estrogenic effect in immature mice at 100 ug
|
Mus musculus
|
79.0
%
|
|
Journal : J. Med. Chem.
Title : Catechol estrogens of the 1,1,2-triphenylbut-1-ene type: relationship between structure, estradiol receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activities.
Year : 1986
Volume : 29
Issue : 8
First Page : 1355
Last Page : 1362
Authors : Schneider MR, Ball H, Schiller CD.
Abstract : 1,1,2-Triphenylbut-1-enes (26-35), which are substituted with one or two 3,4-diacetoxy groups or with one 3,4-diacetoxy and one 3- or 4-acetoxy group in two aromatic rings, were synthesized. The occurring E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study on structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties in the immature mouse, and inhibition of the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, most of the 1,1-disubstituted 1,1,2-triphenylbut-1-enes (29, Z-30, Z,E-31) and (E)-1-(3-acetoxyphenyl)-1-phenyl-2-(3,4-diacetoxyphenyl)but- 1-ene (E-35) as well as its respective Z isomer (Z-35) exerted antiestrogenic properties. Compounds Z-30, Z,E-31, Z-35, and E-35 inhibited the growth of the hormone-dependent MXT tumor. The best antitumor effect without estrogenic side effects during therapy was shown by E-35.
|
In vitro estrogenic effect in immature mice at 10 ug
|
Mus musculus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Catechol estrogens of the 1,1,2-triphenylbut-1-ene type: relationship between structure, estradiol receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activities.
Year : 1986
Volume : 29
Issue : 8
First Page : 1355
Last Page : 1362
Authors : Schneider MR, Ball H, Schiller CD.
Abstract : 1,1,2-Triphenylbut-1-enes (26-35), which are substituted with one or two 3,4-diacetoxy groups or with one 3,4-diacetoxy and one 3- or 4-acetoxy group in two aromatic rings, were synthesized. The occurring E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study on structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties in the immature mouse, and inhibition of the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, most of the 1,1-disubstituted 1,1,2-triphenylbut-1-enes (29, Z-30, Z,E-31) and (E)-1-(3-acetoxyphenyl)-1-phenyl-2-(3,4-diacetoxyphenyl)but- 1-ene (E-35) as well as its respective Z isomer (Z-35) exerted antiestrogenic properties. Compounds Z-30, Z,E-31, Z-35, and E-35 inhibited the growth of the hormone-dependent MXT tumor. The best antitumor effect without estrogenic side effects during therapy was shown by E-35.
|
In vitro estrogenic effect in immature mice at 1 ug
|
Mus musculus
|
43.0
%
|
|
Journal : J. Med. Chem.
Title : Catechol estrogens of the 1,1,2-triphenylbut-1-ene type: relationship between structure, estradiol receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activities.
Year : 1986
Volume : 29
Issue : 8
First Page : 1355
Last Page : 1362
Authors : Schneider MR, Ball H, Schiller CD.
Abstract : 1,1,2-Triphenylbut-1-enes (26-35), which are substituted with one or two 3,4-diacetoxy groups or with one 3,4-diacetoxy and one 3- or 4-acetoxy group in two aromatic rings, were synthesized. The occurring E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study on structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties in the immature mouse, and inhibition of the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, most of the 1,1-disubstituted 1,1,2-triphenylbut-1-enes (29, Z-30, Z,E-31) and (E)-1-(3-acetoxyphenyl)-1-phenyl-2-(3,4-diacetoxyphenyl)but- 1-ene (E-35) as well as its respective Z isomer (Z-35) exerted antiestrogenic properties. Compounds Z-30, Z,E-31, Z-35, and E-35 inhibited the growth of the hormone-dependent MXT tumor. The best antitumor effect without estrogenic side effects during therapy was shown by E-35.
|
In vivo inhibition of hormone-dependent MXT mammary tumor in mice
|
Mus musculus
|
9.8
%
|
|
Journal : J. Med. Chem.
Title : 2-Alkyl-substituted 1,1-bis(4-acetoxyphenyl)-2-phenylethenes. Estrogen receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activity.
Year : 1986
Volume : 29
Issue : 8
First Page : 1494
Last Page : 1498
Authors : Schneider MR.
Abstract : 1,1-Bis(4-acetoxyphenyl)-2-phenylethenes that are substituted with H, CH3, C2H5, n-C3H7, i-C3H7, or CH2CF3 in position 2 were synthesized in order to study the influence of the alkyl side chain on estradiol receptor affinity, estrogenic and antiestrogenic properties, and inhibition of the hormone-dependent MXT mammary carcinoma of the mouse. Furthermore, the double bond of 1,1-bis(4-acetoxyphenyl)-2-phenylbut-1-ene was hydrogenated or epoxidated to yield the corresponding ethane and oxirane derivative. Compounds 14 (R = H), 15 (R = CH3), and 16 (R = C2H5) had the best binding affinities. Lengthening the side chain, hydrogenation, or epoxidation decreased the RBA values. In the immature mouse assay, 15 (R = CH3) and 19 (R = CH2CF3) had the highest uterotrophic activity. There was no correlation between receptor affinity and estrogenic properties. Compounds 14 (R = H), 17 (R = n-C3H7), the ethane 20, and the oxirane 21 had some antiuterotrophic activity in a low dosage. The MXT tumor was best inhibited by compounds 15 (R = CH3), 16 (R = C2H5), and 18 (R = i-C3H7) without significant elevation of the uterine weight determined at the end of the experiment. The antitumor effect of 15, 16, and 18 was significantly better than that of tamoxifen. In this series, a certain estrogenic potency in the immature mouse test seems to be necessary for a good antitumor activity, as all compounds with antiuterotrophic and low uterotrophic properties did not exert any significant tumor-inhibiting effect.
|
In vivo inhibition of uterine growth in hormone-dependent MXT mammary tumor bearing mice
|
Mus musculus
|
87.0
%
|
|
Journal : J. Med. Chem.
Title : 2-Alkyl-substituted 1,1-bis(4-acetoxyphenyl)-2-phenylethenes. Estrogen receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activity.
Year : 1986
Volume : 29
Issue : 8
First Page : 1494
Last Page : 1498
Authors : Schneider MR.
Abstract : 1,1-Bis(4-acetoxyphenyl)-2-phenylethenes that are substituted with H, CH3, C2H5, n-C3H7, i-C3H7, or CH2CF3 in position 2 were synthesized in order to study the influence of the alkyl side chain on estradiol receptor affinity, estrogenic and antiestrogenic properties, and inhibition of the hormone-dependent MXT mammary carcinoma of the mouse. Furthermore, the double bond of 1,1-bis(4-acetoxyphenyl)-2-phenylbut-1-ene was hydrogenated or epoxidated to yield the corresponding ethane and oxirane derivative. Compounds 14 (R = H), 15 (R = CH3), and 16 (R = C2H5) had the best binding affinities. Lengthening the side chain, hydrogenation, or epoxidation decreased the RBA values. In the immature mouse assay, 15 (R = CH3) and 19 (R = CH2CF3) had the highest uterotrophic activity. There was no correlation between receptor affinity and estrogenic properties. Compounds 14 (R = H), 17 (R = n-C3H7), the ethane 20, and the oxirane 21 had some antiuterotrophic activity in a low dosage. The MXT tumor was best inhibited by compounds 15 (R = CH3), 16 (R = C2H5), and 18 (R = i-C3H7) without significant elevation of the uterine weight determined at the end of the experiment. The antitumor effect of 15, 16, and 18 was significantly better than that of tamoxifen. In this series, a certain estrogenic potency in the immature mouse test seems to be necessary for a good antitumor activity, as all compounds with antiuterotrophic and low uterotrophic properties did not exert any significant tumor-inhibiting effect.
|
Concentration giving half of the maximal ATPase activity calculated for the high-affinity binding site of the CHO P-Glycoprotein (P-gp) in two-affinity model
|
Cricetulus griseus
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore model of drugs involved in P-glycoprotein multidrug resistance: explanation of structural variety (hypothesis).
Year : 2002
Volume : 45
Issue : 26
First Page : 5671
Last Page : 5686
Authors : Pajeva IK, Wiese M.
Abstract : A general pharmacophore model of P-glycoprotein (P-gp) drugs is proposed that is based on a highly diverse data set and relates to the verapamil binding site of the protein. It is derived from structurally different drugs using the program GASP. The pharmacophore model consists of two hydrophobic points, three hydrogen bond (HB) acceptor points, and one HB donor point. Pharmacophore patterns of various drugs are obtained, and different binding modes are presumed for some of them. It is concluded that the binding affinity of the drugs depends on the number of the pharmacophore points simultaneously involved in the interaction with P-gp. On the basis of the obtained results, a hypothesis is proposed to explain the broad structural variety of the P-gp substrates and inhibitors: (i) the verapamil binding site of P-gp has several points that can participate in hydrophobic and HB interactions; (ii) different drugs can interact with different receptor points in different binding modes.
|
Percent stimulation or inhibition of protein kinase C III activity for phosphatidylserine (PS) in the presence of [Ca2+].
|
Rattus norvegicus
|
49.0
%
|
|
Journal : J. Med. Chem.
Title : Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation.
Year : 1992
Volume : 35
Issue : 3
First Page : 573
Last Page : 583
Authors : Doré JC, Gilbert J, Bignon E, Crastes de Paulet A, Ojasoo T, Pons M, Raynaud JP, Miquel JF.
Abstract : The response profiles of 36 para-substituted diphenylethylenes (DPEs) and triphenylacrylonitriles (TPEs) have been compared by multivariate analysis. The responses measured were (a) relative binding affinity (RBA) for the cytosol estrogen receptor (ER), (b) ability to promote the growth of the human MCF7 breast cancer cell-line, (c) cytotoxicity in MCF7 cells, and (d) ability to stimulate or inhibit protein kinase C (PKC) III activity under three different conditions of enzyme activation. The prime object of the analysis was to observe the simultaneous influence of diverse combinations of substituents on all these in vitro responses. To do this, the minimum spanning tree (MST) method was used to organize the molecules into a network in which proximate molecules are closely related with regard to their responses whereas remote molecules are distinct. The MST of this population of molecules had four main branches. E2 and its TPE mime were located in a central position within the trunk whereas the tips of the branches tended toward molecules of different specificity, i.e., cytotoxic molecules that bind to ER and interfere with PKC, noncytotoxic molecules that also bind to ER and interfere with PKC but promote cell growth, molecules only active on PKC, and molecules active on all parameters except PKC stimulation. A parallel MST analysis of the relationships among the response parameters themselves confirmed previous conclusions: For this population of molecules, RBAs for ER are fairly closely related to ability to promote MCF7 cell growth and only little to cytotoxicity (Bignon et al. J. Med. Chem. 1989, 32, 2092). Cytotoxicity is much more clearly correlated with inhibition of diacylglycerol-stimulated PKC activity than with RBAs for ER. PKC inhibition differs substantially depending upon whether the substrate is H1 histone or protamine sulfate.
|
Percent stimulation or inhibition of protein kinase C III activity for protamine sulfate in the presence of EGTA.
|
Rattus norvegicus
|
107.0
%
|
|
Journal : J. Med. Chem.
Title : Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation.
Year : 1992
Volume : 35
Issue : 3
First Page : 573
Last Page : 583
Authors : Doré JC, Gilbert J, Bignon E, Crastes de Paulet A, Ojasoo T, Pons M, Raynaud JP, Miquel JF.
Abstract : The response profiles of 36 para-substituted diphenylethylenes (DPEs) and triphenylacrylonitriles (TPEs) have been compared by multivariate analysis. The responses measured were (a) relative binding affinity (RBA) for the cytosol estrogen receptor (ER), (b) ability to promote the growth of the human MCF7 breast cancer cell-line, (c) cytotoxicity in MCF7 cells, and (d) ability to stimulate or inhibit protein kinase C (PKC) III activity under three different conditions of enzyme activation. The prime object of the analysis was to observe the simultaneous influence of diverse combinations of substituents on all these in vitro responses. To do this, the minimum spanning tree (MST) method was used to organize the molecules into a network in which proximate molecules are closely related with regard to their responses whereas remote molecules are distinct. The MST of this population of molecules had four main branches. E2 and its TPE mime were located in a central position within the trunk whereas the tips of the branches tended toward molecules of different specificity, i.e., cytotoxic molecules that bind to ER and interfere with PKC, noncytotoxic molecules that also bind to ER and interfere with PKC but promote cell growth, molecules only active on PKC, and molecules active on all parameters except PKC stimulation. A parallel MST analysis of the relationships among the response parameters themselves confirmed previous conclusions: For this population of molecules, RBAs for ER are fairly closely related to ability to promote MCF7 cell growth and only little to cytotoxicity (Bignon et al. J. Med. Chem. 1989, 32, 2092). Cytotoxicity is much more clearly correlated with inhibition of diacylglycerol-stimulated PKC activity than with RBAs for ER. PKC inhibition differs substantially depending upon whether the substrate is H1 histone or protamine sulfate.
|
Percent stimulation or inhibition of protein kinase C with [Ca2+] for phosphatidylserine and diolein(PS+DO)
|
Rattus norvegicus
|
21.0
%
|
|
Journal : J. Med. Chem.
Title : Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation.
Year : 1992
Volume : 35
Issue : 3
First Page : 573
Last Page : 583
Authors : Doré JC, Gilbert J, Bignon E, Crastes de Paulet A, Ojasoo T, Pons M, Raynaud JP, Miquel JF.
Abstract : The response profiles of 36 para-substituted diphenylethylenes (DPEs) and triphenylacrylonitriles (TPEs) have been compared by multivariate analysis. The responses measured were (a) relative binding affinity (RBA) for the cytosol estrogen receptor (ER), (b) ability to promote the growth of the human MCF7 breast cancer cell-line, (c) cytotoxicity in MCF7 cells, and (d) ability to stimulate or inhibit protein kinase C (PKC) III activity under three different conditions of enzyme activation. The prime object of the analysis was to observe the simultaneous influence of diverse combinations of substituents on all these in vitro responses. To do this, the minimum spanning tree (MST) method was used to organize the molecules into a network in which proximate molecules are closely related with regard to their responses whereas remote molecules are distinct. The MST of this population of molecules had four main branches. E2 and its TPE mime were located in a central position within the trunk whereas the tips of the branches tended toward molecules of different specificity, i.e., cytotoxic molecules that bind to ER and interfere with PKC, noncytotoxic molecules that also bind to ER and interfere with PKC but promote cell growth, molecules only active on PKC, and molecules active on all parameters except PKC stimulation. A parallel MST analysis of the relationships among the response parameters themselves confirmed previous conclusions: For this population of molecules, RBAs for ER are fairly closely related to ability to promote MCF7 cell growth and only little to cytotoxicity (Bignon et al. J. Med. Chem. 1989, 32, 2092). Cytotoxicity is much more clearly correlated with inhibition of diacylglycerol-stimulated PKC activity than with RBAs for ER. PKC inhibition differs substantially depending upon whether the substrate is H1 histone or protamine sulfate.
|
Percent inhibition of estradiol stimulated uterine growth in rats
|
Rattus norvegicus
|
37.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship of antiestrogens. Phenolic analogues of 2,3-diaryl-2H-1-benzopyrans.
Year : 1990
Volume : 33
Issue : 12
First Page : 3222
Last Page : 3229
Authors : Sharma AP, Saeed A, Durani S, Kapil RS.
Abstract : Phenolic analogues of 2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (1), a novel antiestrogen, were synthesized and evaluated for their structure-activity relationship. Incorporation of OH at position 7 was found to improve receptor affinity of the benzopyran while having no effect on its action as an antagonist. Similar substitution of 2-phenyl as well potentiated receptor affinity as well as antagonist activity of the prototype. The monophenol 19 and the diphenol 25 were thus found to be good receptor ligands, devoid of estrogen agonist activity and associated with marked antiestrogenic activity of comparable order. Both caused nearly complete inhibition of the estradiol stimulated uterine growth in rats as well as mice and were thus found to be better antiestrogens than tamoxifen, trioxifen, and LY-117018. A binding-site model for estrogen receptor rationalizing the structure-activity relationship of benzopyrans in relation to that of the triarylethylene and the triarylpropenone antiestrogens has been discussed.
|
Affinity for sigma receptor type 1 of guinea pig using [3H]ifenprodil or (+)-[3H]pentazocine radioligand
|
Cavia porcellus
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of high-affinity ligands of sigma1 receptor, ERG2, and emopamil binding protein by pharmacophore modeling and virtual screening.
Year : 2005
Volume : 48
Issue : 15
First Page : 4754
Last Page : 4764
Authors : Laggner C, Schieferer C, Fiechtner B, Poles G, Hoffmann RD, Glossmann H, Langer T, Moebius FF.
Abstract : ERG2, emopamil binding protein (EBP), and sigma-1 receptor (sigma(1)) are enzymes of sterol metabolism and an enzyme-related protein, respectively, that share high affinity for various structurally diverse compounds. To discover novel high-affinity ligands, pharmacophore models were built with Catalyst based upon a series of 23 structurally diverse chemicals exhibiting K(i) values from 10 pM to 100 microM for all three proteins. In virtual screening experiments, we retrieved drugs that were previously reported to bind to one or several of these proteins and also tested 11 new hits experimentally, of which three, among them raloxifene, had affinities for sigma(1) or EBP of <60 nM. When used to search a database of 3525 biochemicals of intermediary metabolism, a slightly modified ERG2 pharmacophore model successfully retrieved 10 substrate candidates among the top 28 hits. Our results indicate that inhibitor-based pharmacophore models for sigma(1), ERG2, and EBP can be used to screen drug and metabolite databases for chemically diverse compounds and putative endogenous ligands.
|
Affinity for human EMP expressed in ERG2 deficient strain of Saccharomyces cerevisiae using [3H]ifenprodil or (+)-[3H]pentazocine as radioligand
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of high-affinity ligands of sigma1 receptor, ERG2, and emopamil binding protein by pharmacophore modeling and virtual screening.
Year : 2005
Volume : 48
Issue : 15
First Page : 4754
Last Page : 4764
Authors : Laggner C, Schieferer C, Fiechtner B, Poles G, Hoffmann RD, Glossmann H, Langer T, Moebius FF.
Abstract : ERG2, emopamil binding protein (EBP), and sigma-1 receptor (sigma(1)) are enzymes of sterol metabolism and an enzyme-related protein, respectively, that share high affinity for various structurally diverse compounds. To discover novel high-affinity ligands, pharmacophore models were built with Catalyst based upon a series of 23 structurally diverse chemicals exhibiting K(i) values from 10 pM to 100 microM for all three proteins. In virtual screening experiments, we retrieved drugs that were previously reported to bind to one or several of these proteins and also tested 11 new hits experimentally, of which three, among them raloxifene, had affinities for sigma(1) or EBP of <60 nM. When used to search a database of 3525 biochemicals of intermediary metabolism, a slightly modified ERG2 pharmacophore model successfully retrieved 10 substrate candidates among the top 28 hits. Our results indicate that inhibitor-based pharmacophore models for sigma(1), ERG2, and EBP can be used to screen drug and metabolite databases for chemically diverse compounds and putative endogenous ligands.
|
Inhibition of 17-beta-estradiol mediated luciferase transcription in HeLa cells expressing human estrogen receptor alpha; ERE assay
|
Homo sapiens
|
622.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2005
Volume : 48
Issue : 2
First Page : 364
Last Page : 379
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P.
Abstract : We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
|
Inhibition of estrogen-mediated human breast adenocarcinoma (MCF-7) cell proliferation
|
Homo sapiens
|
580.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2005
Volume : 48
Issue : 2
First Page : 364
Last Page : 379
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P.
Abstract : We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
|
Antagonist activity at ER receptor assessed as inhibition of 17-alpha-ethynylestradiol-induced increase in uterine weight of Sprague-Dawley rat at 3 mg/kg/day, po
|
Rattus norvegicus
|
49.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Rapid synthesis of 4-benzylidene and 4-[bis-(4-methoxyphenyl)-methylene-2-substituted phenyl-benzopyrans as potential selective estrogen receptor modulators (SERMs) using McMurry coupling reaction.
Year : 2006
Volume : 16
Issue : 23
First Page : 6006
Last Page : 6012
Authors : Gupta A, Dwivedy A, Keshri G, Sharma R, Balapure AK, Singh MM, Ray S.
Abstract : 7-Methoxy-4-(4-methoxybenzylidene)-2-substituted phenyl-benzopyrans I and 4-[bis-(4-methoxyphenyl)-methylene-2-substituted phenyl-benzopyrans II carrying different alkylamino residues, designed as estrogen receptor (ER) binding ligands, were successfully synthesized through the McMurry coupling reaction of substituted benzaldehyde/substituted benzophenones and 2-hydroxyphenyl-7-methoxy-chroman-4-one in presence of lithium aluminum hydride and titanium (IV) chloride (LAH-TiCl(4)). Self-coupling of carbonyl reactants led to the formation of several side products. The prototypes were evaluated for their relative binding affinity (RBA), as well as their estrogenic and antiestrogenic activities. High order of estrogenic activity (>50% gain) observed with compounds 3, 7a, 7b, 7c, 8, and 10a and also their partial estrogen antagonistic activity (> or =15%) at the uterine level points toward successful designing of the compounds. Compounds 4, 7a, 7b, 7c, and 10a also possessed significant anticancer activity against human adenocarcinoma cell line (MCF-7 cell line) that may be related to their estrogen-dependent action.
|
Growth inhibition of human HL60 cells after 4 hrs by MTT assay
|
Homo sapiens
|
5.9
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : An expeditious synthesis of tamoxifen, a representative SERM (selective estrogen receptor modulator), via the three-component coupling reaction among aromatic aldehyde, cinnamyltrimethylsilane, and beta-chlorophenetole.
Year : 2007
Volume : 15
Issue : 24
First Page : 7599
Last Page : 7617
Authors : Shiina I, Sano Y, Nakata K, Suzuki M, Yokoyama T, Sasaki A, Orikasa T, Miyamoto T, Ikekita M, Nagahara Y, Hasome Y.
Abstract : Two new synthetic pathways to the anti-cancer agent tamoxifen and its derivatives were developed. The first route involved the aldol reaction of benzyl phenyl ketone with acetaldehyde followed by Friedel-Crafts substitution with anisole in the presence of Cl(2)Si(OTf)(2) to produce 1,1,2-triaryl-3-acetoxybutane, a precursor of the tamoxifen derivatives. The second one utilized the novel three-component coupling reaction among aromatic aldehydes, cinnamyltrimethylsilane, and aromatic nucleophiles using HfCl(4) as a Lewis acid catalyst to produce 3,4,4-triarylbutene, that is also a valuable intermediate of the tamoxifen derivatives. The former strategy requires a total of 10 steps from the aldol formation to the final conversion to tamoxifen, whereas the latter needs only three or four steps to produce tamoxifen and droloxifene including the installation of the side-chain moiety and the base-induced double-bond migration to form the tetra-substituted olefin structure. This synthetic strategy seems to serve as a new and practical pathway to prepare not only the tamoxifen derivatives but also the other SERMs (selective estrogen receptor modulators) including estrogen-dependent breast cancer and osteoporosis agents.
|
Displacement of fluorescein labeled estradiol from human recombinant ERalpha expressed in baculovirus infected insect cells by fluorescence polarization assay
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation, structural-activity relationship, and docking study for a series of benzoxepin-derived estrogen receptor modulators.
Year : 2008
Volume : 16
Issue : 21
First Page : 9554
Last Page : 9573
Authors : Barrett I, Meegan MJ, Hughes RB, Carr M, Knox AJ, Artemenko N, Golfis G, Zisterer DM, Lloyd DG.
Abstract : The estrogen receptors ERalpha and ERbeta are recognized as important pharmaceutical targets for a variety of diseases including osteoporosis and breast cancer. A series of novel benzoxepin-derived compounds are described as potent selective modulators of the human estrogen receptor modulators (SERMs). We report the antiproliferative effects of these compounds on human MCF-7 breast tumor cells. These heterocyclic compounds contain the triarylethylene arrangement as exemplified by tamoxifen, conformationally restrained through the incorporation of the benzoxepin ring system. The compounds demonstrate potency at nanomolar concentrations in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity together with low nanomolar binding affinity for the estrogen receptor. The compounds also demonstrate potent antiestrogenic properties in the human uterine Ishikawa cell line. The effect of a number of functional group substitutions on the ER binding properties of the benzoxepin molecular scaffold is examined through a detailed docking and 2D-QSAR computational investigation. The best QSAR model developed for ERalphabeta selectivity yielded R(2) of 0.84 with an RMSE for the training set of 0.30. The predictive quality of the model was Q(2) of 0.72 and RMSE of 0.18 for the test set. One particular compound bearing a 4-fluoro substituent, exhibits 15-fold selectivity for ERbeta and both our docking and QSAR studies converge on the correlation between enhanced lipophilicity and enhanced ERbeta binding for this benzoxepin ring scaffold.
|
Displacement of fluorescein labeled estradiol from human recombinant ERbeta expressed in baculovirus infected insect cells by fluorescence polarization assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation, structural-activity relationship, and docking study for a series of benzoxepin-derived estrogen receptor modulators.
Year : 2008
Volume : 16
Issue : 21
First Page : 9554
Last Page : 9573
Authors : Barrett I, Meegan MJ, Hughes RB, Carr M, Knox AJ, Artemenko N, Golfis G, Zisterer DM, Lloyd DG.
Abstract : The estrogen receptors ERalpha and ERbeta are recognized as important pharmaceutical targets for a variety of diseases including osteoporosis and breast cancer. A series of novel benzoxepin-derived compounds are described as potent selective modulators of the human estrogen receptor modulators (SERMs). We report the antiproliferative effects of these compounds on human MCF-7 breast tumor cells. These heterocyclic compounds contain the triarylethylene arrangement as exemplified by tamoxifen, conformationally restrained through the incorporation of the benzoxepin ring system. The compounds demonstrate potency at nanomolar concentrations in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity together with low nanomolar binding affinity for the estrogen receptor. The compounds also demonstrate potent antiestrogenic properties in the human uterine Ishikawa cell line. The effect of a number of functional group substitutions on the ER binding properties of the benzoxepin molecular scaffold is examined through a detailed docking and 2D-QSAR computational investigation. The best QSAR model developed for ERalphabeta selectivity yielded R(2) of 0.84 with an RMSE for the training set of 0.30. The predictive quality of the model was Q(2) of 0.72 and RMSE of 0.18 for the test set. One particular compound bearing a 4-fluoro substituent, exhibits 15-fold selectivity for ERbeta and both our docking and QSAR studies converge on the correlation between enhanced lipophilicity and enhanced ERbeta binding for this benzoxepin ring scaffold.
|
Antiestrogenic activity in human Ishikawa cells assessed as inhibition of estrogen-induced alkaline phosphatase activity after 72 hrs
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation, structural-activity relationship, and docking study for a series of benzoxepin-derived estrogen receptor modulators.
Year : 2008
Volume : 16
Issue : 21
First Page : 9554
Last Page : 9573
Authors : Barrett I, Meegan MJ, Hughes RB, Carr M, Knox AJ, Artemenko N, Golfis G, Zisterer DM, Lloyd DG.
Abstract : The estrogen receptors ERalpha and ERbeta are recognized as important pharmaceutical targets for a variety of diseases including osteoporosis and breast cancer. A series of novel benzoxepin-derived compounds are described as potent selective modulators of the human estrogen receptor modulators (SERMs). We report the antiproliferative effects of these compounds on human MCF-7 breast tumor cells. These heterocyclic compounds contain the triarylethylene arrangement as exemplified by tamoxifen, conformationally restrained through the incorporation of the benzoxepin ring system. The compounds demonstrate potency at nanomolar concentrations in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity together with low nanomolar binding affinity for the estrogen receptor. The compounds also demonstrate potent antiestrogenic properties in the human uterine Ishikawa cell line. The effect of a number of functional group substitutions on the ER binding properties of the benzoxepin molecular scaffold is examined through a detailed docking and 2D-QSAR computational investigation. The best QSAR model developed for ERalphabeta selectivity yielded R(2) of 0.84 with an RMSE for the training set of 0.30. The predictive quality of the model was Q(2) of 0.72 and RMSE of 0.18 for the test set. One particular compound bearing a 4-fluoro substituent, exhibits 15-fold selectivity for ERbeta and both our docking and QSAR studies converge on the correlation between enhanced lipophilicity and enhanced ERbeta binding for this benzoxepin ring scaffold.
|
Cytotoxicity against human HT-29 cells by alamar blue assay
|
Homo sapiens
|
1.86
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Isolation and biological evaluation of filiformin, plakortide F, and plakortone G from the Caribbean sponge Plakortis sp.
Year : 2001
Volume : 64
Issue : 11
First Page : 1477
Last Page : 1479
Authors : Gochfeld DJ, Hamann MT.
Abstract : The bioassay- and spectroscopic-guided fractionation of the antimalarial extract from a Jamaican sponge, Plakortis sp., resulted in the isolation of three metabolites. The previously reported bromoaromatic filiformin (1) was obtained from our sample of Plakortis sp., and the potential origins of this compound are discussed. The peroxide-containing metabolite, plakortide F (2), is a more typical Plakortis metabolite and was shown to exhibit significant activity against Plasmodium falciparum in vitro. The isolation, structure, and bioactivity of a new lactone, plakortone G (3), are also reported.
|
Cytotoxicity against human A549 cells by alamar blue assay
|
Homo sapiens
|
1.86
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Isolation and biological evaluation of filiformin, plakortide F, and plakortone G from the Caribbean sponge Plakortis sp.
Year : 2001
Volume : 64
Issue : 11
First Page : 1477
Last Page : 1479
Authors : Gochfeld DJ, Hamann MT.
Abstract : The bioassay- and spectroscopic-guided fractionation of the antimalarial extract from a Jamaican sponge, Plakortis sp., resulted in the isolation of three metabolites. The previously reported bromoaromatic filiformin (1) was obtained from our sample of Plakortis sp., and the potential origins of this compound are discussed. The peroxide-containing metabolite, plakortide F (2), is a more typical Plakortis metabolite and was shown to exhibit significant activity against Plasmodium falciparum in vitro. The isolation, structure, and bioactivity of a new lactone, plakortone G (3), are also reported.
|
Cytotoxicity against human SK-MEL-28 cells by alamar blue assay
|
Homo sapiens
|
1.86
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Isolation and biological evaluation of filiformin, plakortide F, and plakortone G from the Caribbean sponge Plakortis sp.
Year : 2001
Volume : 64
Issue : 11
First Page : 1477
Last Page : 1479
Authors : Gochfeld DJ, Hamann MT.
Abstract : The bioassay- and spectroscopic-guided fractionation of the antimalarial extract from a Jamaican sponge, Plakortis sp., resulted in the isolation of three metabolites. The previously reported bromoaromatic filiformin (1) was obtained from our sample of Plakortis sp., and the potential origins of this compound are discussed. The peroxide-containing metabolite, plakortide F (2), is a more typical Plakortis metabolite and was shown to exhibit significant activity against Plasmodium falciparum in vitro. The isolation, structure, and bioactivity of a new lactone, plakortone G (3), are also reported.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
72.1
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Antiproliferative activity against human MCF7 cells after 24 hrs by MTS assay
|
Homo sapiens
|
580.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and preliminary biological evaluation of new carbon-11 labeled tetrahydroisoquinoline derivatives as SERM radioligands for PET imaging of ER expression in breast cancer.
Year : 2008
Volume : 43
Issue : 10
First Page : 2211
Last Page : 2219
Authors : Gao M, Wang M, Miller KD, Sledge GW, Zheng QH.
Abstract : The estrogen receptors (ERs) are attractive targets in the treatment of breast cancer and the development of receptor-based breast cancer imaging agents for diagnostic use in biomedical imaging technique positron emission tomography (PET). Tetrahydroisoquinoline derivatives are a class of selective estrogen receptor modulators (SERMs) with high binding affinity and specificity exhibiting up to 50 folds for ERalpha over ERbeta. New carbon-11 labeled tetrahydroisoquinoline derivatives, [11C]methyl 1-(2-(4-(2-(4-fluorophenyl)-6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenoxy)ethyl)piperidine-4-carboxylate ([11C]10a) and [11C]methyl 1-(2-(4-(2-(4-chlorophenyl)-6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenoxy)ethyl)piperidine-4-carboxylate ([11C]10b), have been first designed, synthesized and evaluated. The target tracers were prepared by O-[11C]methylation of their corresponding precursors using [11C]CH3OTf and isolated by solid-phase extraction (SPE) purification procedure in 40-60% radiochemical yields, which were decay corrected to the end of bombardment (EOB), based on [11C]CO2. The overall synthesis time was 15-20 min from EOB. The radiochemical purity was >99%, and specific activity was in a range of 74-111GBq/micromol at the end of synthesis (EOS). Preliminary findings from in vitro biological assay indicate that the synthesized derivatives displayed similar potencies in the MCF-7 human breast cancer cell line in comparison with 4-hydroxytamoxifen, a well-known potent SERM. These results encourage further in vivo evaluation of carbon-11 labeled tetrahydroisoquinoline derivatives as new potential SERM radioligands for PET imaging of ER expression in breast cancer.
|
Antiestrogenic activity in human T47D cells expressing estrogen receptor assessed as estrogen-dependent transcription by luciferase reporter gene assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-Benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1).
Year : 2009
Volume : 19
Issue : 4
First Page : 1218
Last Page : 1223
Authors : Allan M, Manku S, Therrien E, Nguyen N, Styhler S, Robert MF, Goulet AC, Petschner AJ, Rahil G, Robert Macleod A, Déziel R, Besterman JM, Nguyen H, Wahhab A.
Abstract : A series of N-benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides targeting co-activator associated arginine methyltransferase 1 (CARM1) have been designed and synthesized. The potency of these inhibitors was influenced by the nature of the heteroaryl fragment with the thiophene analogues being superior to thiazole, pyridine, isoindoline and benzofuran based inhibitors.
|
Cytotoxicity against rat L6 cells
|
Rattus norvegicus
|
4.9
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : New potent imidazoisoquinolinone derivatives as anti-Trypanosoma cruzi agents: biological evaluation and structure-activity relationships.
Year : 2009
Volume : 17
Issue : 4
First Page : 1437
Last Page : 1444
Authors : Bollini M, Casal JJ, Alvarez DE, Boiani L, González M, Cerecetto H, Bruno AM.
Abstract : A series of novel benzoimidazo and N-aryl-5-oxo-imidazo[1,2-b]isoquinoline-10-carbothioamides was developed. All the compounds were evaluated for their in vitro action against the epimastigote form of Trypanosoma cruzi. Four of them showed higher activity than Nifurtimox. Their unspecific cytotoxicity was evaluated using HeLa and L6 cells, being non-toxic at concentrations at least 15 and 200 times higher than that of T. cruzi IC(50.) To gain insight into the mechanism of action, their DNA binding properties and reactivity with glutathione were studied, and QSAR study was performed.
|
Antiestrogenic activity in human Ishikawa cells assessed as inhibition of estrogen-induced alkaline phosphatase activity after 4 days by ELISA
|
Homo sapiens
|
420.0
nM
|
|
Journal : J. Nat. Prod.
Title : Activity-guided isolation of steroidal alkaloid antiestrogen-binding site inhibitors from Pachysandra procumbens.
Year : 1998
Volume : 61
Issue : 10
First Page : 1257
Last Page : 1262
Authors : Chang LC, Bhat KP, Pisha E, Kennelly EJ, Fong HH, Pezzuto JM, Kinghorn AD.
Abstract : Four novel steroidal alkaloids, (+)-(20S)-20-(dimethylamino)-3-(3'alpha-isopropyl)-lactam-5alpha-+ ++preg n-2-en-4-one (1), (+)-(20S)-20-(dimethylamino)-16alpha-hydroxy-3-(3'alpha-isopropyl) -la ctam-5alpha-pregn-2-en-4-one (2), (+)-(20S)-3-(benzoylamino)-20-(dimethylamino)-5alpha-pregn-2-en-++ +4beta -yl acetate (3), and (+)-(20S)-2alpha-hydroxy-20-(dimethylamino)-3beta-phthalimido-5 alpha- pregnan-4beta-yl acetate (4), as well as five known compounds, (-)-pachyaximine A (5), (+)-spiropachysine (6), (+)-axillaridine A (7), (+)-epipachysamine D (8), and (+)-pachysamine B (9), were isolated from Pachysandra procumbens, using a bioassay-guided fractionation based on inhibition of 3H-tamoxifen binding at the antiestrogen binding site (AEBS). Compounds 1-7 and 9 demonstrated significant activity as AEBS-inhibitory agents, and compounds 3, 5 and 9 were found to potentiate significantly the antiestrogenic effect mediated by tamoxifen in cultured Ishikawa cells. The structure elucidation of compounds 1-4 was carried out by spectral data interpretation.
|
Inhibition of human aquaporin 4 M23 isoform expressed in Xenopus laevis oocytes at 20 uM
|
Homo sapiens
|
71.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of aquaporin 4 inhibitors using in vitro and in silico methods.
Year : 2009
Volume : 17
Issue : 1
First Page : 411
Last Page : 417
Authors : Huber VJ, Tsujita M, Nakada T.
Abstract : The in vitro inhibitory effects and in silico docking energies of 18 compounds with respect to aquaporin 4 (AQP4) were investigated. More than half of the compounds tested showed inhibitory activity in the in vitro functional assay and included the 5-HT(1B/1D) agonists sumatriptan, and rizatriptan. Moreover, the observed inhibitory activity of the compounds used in this study at 20 microM showed a strong correlation with their in silico docking energies, r(2)=0.64, which was consistent with that found in previous studies. The AQP4 inhibitory IC(50) values of three compounds, 2-(nicotinamido)-1,3,4-thiadiazole, sumatriptan and rizatriptan, were subsequently found to be 3, 11, and 2 microM, respectively.
|
Estrogenic antagonistic activity in bilaterally ovariectomized Sprague-Dawley rat assessed as inhibition of ethynylesterol-induced uterine weight at 10 mg/kg, po once daily for 3 days measured on day 31 of age
|
Rattus norvegicus
|
27.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of 2,3,4-triarylbenzopyran derivatives as SERM and therapeutic agent for breast cancer.
Year : 2009
Volume : 17
Issue : 19
First Page : 6832
Last Page : 6840
Authors : Kumar S, Deshpande S, Chandra V, Kitchlu S, Dwivedi A, Nayak VL, Konwar R, Prabhakar YS, Sahu DP.
Abstract : A novel class of 2,3,4-triarylbenzopyrans has been synthesized and were evaluated for their selective estrogen receptor modulation activity and as a therapeutic agent for breast cancer. Among the compounds synthesized, compounds 11a and 12c exhibited 73.91% and 69.24% inhibition as estrogen antagonistic activity, respectively. Compound 12a showed the lowest IC(50) at 6.97 microM against MCF-7 and 11f showed the lowest IC(50) value of 5.6 microM against MDA-MB-231 cell line in spite of their low receptor binding affinity implicating these compounds probably act through ER independent mechanism.
|
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 0.3 uM after 7 hrs
|
Homo sapiens
|
8.9
%
|
|
Journal : J. Med. Chem.
Title : Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
Year : 2009
Volume : 52
Issue : 23
First Page : 7488
Last Page : 7502
Authors : Bellavance E, Luu-The V, Poirier D.
Abstract : 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
|
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 3 uM after 7 hrs
|
Homo sapiens
|
3.2
%
|
|
Journal : J. Med. Chem.
Title : Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
Year : 2009
Volume : 52
Issue : 23
First Page : 7488
Last Page : 7502
Authors : Bellavance E, Luu-The V, Poirier D.
Abstract : 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
|
Uterotropic activity in rat assessed as inhibition of estrone-stimulated uterine weight at 1 mg/kg, po QD after 3 days
|
Rattus norvegicus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.
Year : 2009
Volume : 52
Issue : 23
First Page : 7544
Last Page : 7569
Authors : Jain N, Xu J, Kanojia RM, Du F, Jian-Zhong G, Pacia E, Lai MT, Musto A, Allan G, Reuman M, Li X, Hahn D, Cousineau M, Peng S, Ritchie D, Russell R, Lundeen S, Sui Z.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
|
Uterotropic activity in rat assessed as stimulation of estrone-induced uterine weight at 1 mg/kg, po QD after 3 days
|
Rattus norvegicus
|
109.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.
Year : 2009
Volume : 52
Issue : 23
First Page : 7544
Last Page : 7569
Authors : Jain N, Xu J, Kanojia RM, Du F, Jian-Zhong G, Pacia E, Lai MT, Musto A, Allan G, Reuman M, Li X, Hahn D, Cousineau M, Peng S, Ritchie D, Russell R, Lundeen S, Sui Z.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
|
Inhibition of PKC at 0.2 mM after 90 mins by ELISA
|
None
|
25.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Endoxifen is a new potent inhibitor of PKC: a potential therapeutic agent for bipolar disorder.
Year : 2010
Volume : 20
Issue : 8
First Page : 2665
Last Page : 2667
Authors : Ali SM, Ahmad A, Shahabuddin S, Ahmad MU, Sheikh S, Ahmad I.
Abstract : Protein kinase C (PKC) plays a major role in regulation of both pre and postsynaptic neurotransmission. Excessive activation of PKC results in symptoms related to bipolar disorder. Tamoxifen, a widely used breast cancer drug is known to inhibit PKC and demonstrate antimanic properties in human. We describe herein the synthesis of endoxifen, a tamoxifen active metabolite and compared its PKC inhibitory activity with that of tamoxifen. Endoxifen exhibited fourfold higher potency compared to tamoxifen.
|
Inhibition of PKC at 0.1 mM after 90 mins by ELISA
|
None
|
14.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Endoxifen is a new potent inhibitor of PKC: a potential therapeutic agent for bipolar disorder.
Year : 2010
Volume : 20
Issue : 8
First Page : 2665
Last Page : 2667
Authors : Ali SM, Ahmad A, Shahabuddin S, Ahmad MU, Sheikh S, Ahmad I.
Abstract : Protein kinase C (PKC) plays a major role in regulation of both pre and postsynaptic neurotransmission. Excessive activation of PKC results in symptoms related to bipolar disorder. Tamoxifen, a widely used breast cancer drug is known to inhibit PKC and demonstrate antimanic properties in human. We describe herein the synthesis of endoxifen, a tamoxifen active metabolite and compared its PKC inhibitory activity with that of tamoxifen. Endoxifen exhibited fourfold higher potency compared to tamoxifen.
|
Antiproliferative activity against human MCF7 cells assessed as viable cells at 100 uM after 24 hrs by MTT assay
|
Homo sapiens
|
93.33
%
|
|
Journal : J. Med. Chem.
Title : Discovery of potent ligands for estrogen receptor beta by structure-based virtual screening.
Year : 2010
Volume : 53
Issue : 14
First Page : 5361
Last Page : 5365
Authors : Shen J, Tan C, Zhang Y, Li X, Li W, Huang J, Shen X, Tang Y.
Abstract : With virtual screening based on a structure optimized through molecular dynamics (MD) and bioassays, 18 potent ligands of estrogen receptor (ER) beta were discovered from 70 purchased compounds here. Among them, dual profile was observed in two ligands (1a and 1b), as agonists for ERbeta and antagonists for ERalpha, and they might serve as lead compounds for selective ER modulators. The results also suggest that structures optimized through MD are applicable to lead discovery.
|
Antiproliferative activity against human MDA-MB-231 cells by MTT assay
|
Homo sapiens
|
660.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new cis-fused tetrahydrochromeno[4,3-b]quinolines and their antiproliferative activity studies against MDA-MB-231 and MCF-7 breast cancer cell lines.
Year : 2010
Volume : 20
Issue : 11
First Page : 3259
Last Page : 3264
Authors : Nagaiah K, Venkatesham A, Srinivasa Rao R, Saddanapu V, Yadav JS, Basha SJ, Sarma AV, Sridhar B, Addlagatta A.
Abstract : New cis-fused tetrahydrochromeno[4,3-b]quinolines have been synthesized by intramolecular [4+2] imino-Diels-Alder reactions of 2-azadienes derived in situ from aromatic amines and 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones in the presence of 20mol% Yb(OTf)(3) in acetonitrile under reflux conditions in good to excellent yields. The structures were established by spectroscopic data and further confirmed by X-ray diffraction analysis. These compounds were evaluated for their antiproliferative activity against MDA-MB-231 and MCF-7 breast cancer cells. The results showed that compounds 3e, 3f, and 3k exhibit significant antiproliferative activity against MCF-7 breast cancer cells and low inhibitory activity against MDA-MB-231 breast cancer cell lines. Compound 3h displayed activity as comparable to tamoxifen on both the cell lines.
|
Inhibition of LuxR-dependent quorum sensing in Vibrio fischeri assessed as reduction of 3-oxo-C6-HSL-induced bioluminescence intensity at 20 uM
|
Aliivibrio fischeri
|
73.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : LuxR-dependent quorum sensing: computer aided discovery of new inhibitors structurally unrelated to N-acylhomoserine lactones.
Year : 2010
Volume : 20
Issue : 15
First Page : 4355
Last Page : 4358
Authors : Soulère L, Sabbah M, Fontaine F, Queneau Y, Doutheau A.
Abstract : A virtual screening, involving flexible docking sequences within the LuxR, TraR and LasR binding sites, was used as a structural binding sites similarity filter to specifically target conserved residues in the proteins of the LuxR family (namely Tyr62, Trp66, Tyr70, Asp79, Trp94 for LuxR). This docking-based screening, employing a genetic algorithm, was performed on a 2344 chemical compounds library, together with empirical binding free energy (DeltaG(bind)) calculations. Docking results were analysed, and the compounds detected with reproducible low DeltaG(bind) values or identified as being in the top 120 for most of the docking sequences, were selected as hits candidates which interact with conserved residues. Biological evaluation with LuxR-dependent quorum sensing led to the discovery of some new inhibitors, namely tamoxifen, sertraline, pimethixene, terfenadine, fendiline and calmidazolium. Notably, calmidazolium was identified as one of the most potent AHL-structurally unrelated inhibitors of LuxR-dependent quorum sensing, with an IC(50) value of 7.0+/-0.2 microM.
|
Inhibition of LuxR-dependent quorum sensing in Vibrio fischeri assessed as reduction of 3-oxo-C6-HSL-induced bioluminescence intensity at 40 uM
|
Aliivibrio fischeri
|
53.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : LuxR-dependent quorum sensing: computer aided discovery of new inhibitors structurally unrelated to N-acylhomoserine lactones.
Year : 2010
Volume : 20
Issue : 15
First Page : 4355
Last Page : 4358
Authors : Soulère L, Sabbah M, Fontaine F, Queneau Y, Doutheau A.
Abstract : A virtual screening, involving flexible docking sequences within the LuxR, TraR and LasR binding sites, was used as a structural binding sites similarity filter to specifically target conserved residues in the proteins of the LuxR family (namely Tyr62, Trp66, Tyr70, Asp79, Trp94 for LuxR). This docking-based screening, employing a genetic algorithm, was performed on a 2344 chemical compounds library, together with empirical binding free energy (DeltaG(bind)) calculations. Docking results were analysed, and the compounds detected with reproducible low DeltaG(bind) values or identified as being in the top 120 for most of the docking sequences, were selected as hits candidates which interact with conserved residues. Biological evaluation with LuxR-dependent quorum sensing led to the discovery of some new inhibitors, namely tamoxifen, sertraline, pimethixene, terfenadine, fendiline and calmidazolium. Notably, calmidazolium was identified as one of the most potent AHL-structurally unrelated inhibitors of LuxR-dependent quorum sensing, with an IC(50) value of 7.0+/-0.2 microM.
|
Displacement of [2,4,6,7-3H]estradiol from human ERalpha expressed in HeLa cells after 18 hrs by liquid scintillation counting
|
Homo sapiens
|
31.19
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Genomic action of permanently charged tamoxifen derivatives via estrogen receptor-alpha.
Year : 2010
Volume : 18
Issue : 15
First Page : 5593
Last Page : 5601
Authors : Rivera-Guevara C, Pérez-Alvarez V, García-Becerra R, Ordaz-Rosado D, Morales-Ríos MS, Hernández-Gallegos E, Cooney AJ, Bravo-Gómez ME, Larrea F, Camacho J.
Abstract : Tamoxifen is a selective estrogen receptor modulator widely used in oncology and reproductive endocrinology. In order to decrease its non-desirable effects and elucidate mechanisms of action, permanently charged tamoxifen derivatives (PCTDs) have been reported. Whether PCTDs have genomic effects remains controversial. Since the clinical relevance of tamoxifen, the necessity to have new anticancer drugs, and in order to gain insights into the mechanisms of action of PCTDs, we obtained six quaternary ammonium salts derived from tamoxifen including three new compounds. We characterized them by nuclear magnetic resonance, X-ray diffraction, electron microscopy, and/or high performance liquid chromatography, and detected them in cell lysates by liquid chromatography coupled to mass spectrometry. We evaluated their binding to estrogen receptor-alpha (ERalpha, their effect on the transcriptional activity mediated by ERalpha (gene reporter assays), and the proliferation of cancer cells (MCF-7 and cells from a cervical cancer primary culture). Structural studies demonstrated the expected identity of the molecules. All PCTDs did bind to ERalpha, one of them induced ERalpha-mediated transcription while two others inhibited such genomic action. Accordingly, PCTDs were detected in cell lysates. PCTDs inhibited cell proliferation, noteworthy, two of them displayed higher inhibition than tamoxifen. Structure-activity analysis suggests that PCTDs permanent positive charge and the length of the aliphatic chain might be associated to the biological responses studied. We suggest genomic effects as a mechanism of action of PCTDs. The experimental approaches here used could lead to a better design of new therapeutic molecules and help to elucidate molecular mechanisms of new anticancer drugs.
|
Cytotoxicity against human MCF7 cells after 48 hrs by SRB assay
|
Homo sapiens
|
8.31
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and in vitro anti-tumor activity of new oxadiazole thioglycosides.
Year : 2011
Volume : 46
Issue : 1
First Page : 229
Last Page : 235
Authors : Abu-Zaied MA, El-Telbani EM, Elgemeie GH, Nawwar GA.
Abstract : A facile, convenient and high yielding synthesis of novel thioglycosides incorporating 1,3,4-oxadiazole, triazole and or triazine moieties from readily available starting materials has been described. The key step of this protocol is the formation of 3-isobutyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3) via condensation between methyl iso-butyl ketone and phenylhydrazine followed by application of Vilsmeier-Haack reaction. 3 was converted either to 1,3,4-oxadiazole derivative or condensed with O-aminothiols to give the bases 8, 19 and 20 in good yields, respectively. The aglycons 8, 19, and 20 were coupled with different activated halosugars in the presence of basic medium. Pharmacological evaluation of compounds 8, 14, 16 and 22 in vitro against 2-cell lines MCF-7 (breast) and HEPG2 (liver) revealed them to possess high anti-tumor activities with IC(50) values ranging from 2.67-20.25 (μg/mL) for breast cell line (MCF-7) and 4.62-43.6 (μg/mL) for liver cell line (HEPG2). None of the tested compounds exhibited any toxicity in doses up to 500 mg kg(-1) of the animal body weight.
|
Mechanism based inhibition of human cytochrome P450 3A4 measured by testosterone 6-beta hydroxylation
|
Homo sapiens
|
200.0
nM
|
|
Journal : Curr. Drug Metab.
Title : Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.
Year : 2005
Volume : 6
Issue : 1
First Page : 413
Last Page : 454
Authors : Fontana E, Dansette PM, Poli SM.
Abstract : The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.
|
Mechanism based inhibition of human cytochrome P450 2B6 measured by 7-EFC O-deethylation
|
Homo sapiens
|
900.0
nM
|
|
Journal : Curr. Drug Metab.
Title : Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.
Year : 2005
Volume : 6
Issue : 1
First Page : 413
Last Page : 454
Authors : Fontana E, Dansette PM, Poli SM.
Abstract : The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.
|
Antiestrogenic activity in Sprague-Dawley rat assessed as inhibition of uterine weight gain administered as po daily once for 3 days relative to 17alpha-ethynylestradiol
|
Rattus norvegicus
|
49.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of 1,3-biarylsulfanyl derivatives as new anti-breast cancer agents.
Year : 2011
Volume : 19
Issue : 18
First Page : 5409
Last Page : 5419
Authors : Kumar A, Tripathi VD, Kumar P, Gupta LP, Akanksha, Trivedi R, Bid H, Nayak VL, Siddiqui JA, Chakravarti B, Saxena R, Dwivedi A, Siddiquee MI, Siddiqui U, Konwar R, Chattopadhyay N.
Abstract : A new series of 1,3-biarylsulfanyl derivatives (homodibenzyl core motif) have been designed and synthesized as new estrogen receptor ligands by chopping benzothiophene core of raloxifene to engender seco-raloxifene scaffold. All the synthesized compounds were screened for anti-proliferative, anti-osteoporotic, and anti-implantation activity. Compounds (35, 36) having basic amino anti-estrogenic side chain were exhibiting potential anti-proliferative activity in MCF-7, MDA-MB-231 and ishikawa cell lines. Some of the synthesized compounds having homodibenzyl motif (5, 8, 10) have shown moderate anti-osteoporotic activity.
|
DRUGMATRIX: Muscarinic M1 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
681.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M3 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
630.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M4 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
672.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Potassium Channel HERG radioligand binding (ligand: [3H] Astemizole)
|
None
|
967.0
nM
|
|
DRUGMATRIX: Potassium Channel HERG radioligand binding (ligand: [3H] Astemizole)
|
None
|
792.2
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
726.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2C radioligand binding (ligand: [3H] Mesulergine)
|
None
|
460.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2C radioligand binding (ligand: [3H] Mesulergine)
|
None
|
241.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Sigma1 radioligand binding (ligand: [3H] Haloperidol)
|
None
|
21.0
nM
|
|
DRUGMATRIX: Sigma1 radioligand binding (ligand: [3H] Haloperidol)
|
None
|
8.714
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Sigma2 radioligand binding (ligand: [3H] Ifenprodil)
|
Rattus norvegicus
|
619.0
nM
|
|
DRUGMATRIX: Sigma2 radioligand binding (ligand: [3H] Ifenprodil)
|
Rattus norvegicus
|
381.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Thromboxane Synthetase enzyme inhibition (substrate: PGH2)
|
Homo sapiens
|
916.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Dopamine D3 radioligand binding (ligand: [3H] Spiperone)
|
None
|
364.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Cytotoxicity against human MCF7 cells after 48 hrs by SRB assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and anticancer activity of 2-benzylidene indanones through inhibiting tubulin polymerization.
Year : 2012
Volume : 20
Issue : 9
First Page : 3049
Last Page : 3057
Authors : Prakasham AP, Saxena AK, Luqman S, Chanda D, Kaur T, Gupta A, Yadav DK, Chanotiya CS, Shanker K, Khan F, Negi AS.
Abstract : In an attempt to discover a potent and selective anticancer agent, gallic acid has been modified to benzylidene indanones as tubulin polymerization inhibitors. These compounds were evaluated against several human cancer cell lines and also evaluated for inhibition of tubulin polymerase in in vitro assays. Three of the analogues exhibited strong cytotoxicity against human cancer cell lines IC(50)=10-880 nM and also showed tubulin polymerization inhibition (IC(50)=0.62-2.04 μM). Compound 9j, the best candidate of the series was found to be non-toxic in acute oral toxicity in Swiss-albino mice up to 1000 mg/kg dose.
|
Displacement of [3H]estradiol from ERbeta after 4 hrs by scintillation counting
|
None
|
0.51
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Hydrophobic Interactions Improve Selectivity to ERα for Ben-zothiophene SERMs.
Year : 2012
Volume : 3
Issue : 3
First Page : 207
Last Page : 210
Authors : Chalmers MJ, Wang Y, Novick S, Sato M, Bryant HU, Montrose-Rafizdeh C, Griffin PR, Dodge JA.
Abstract : The discovery, pharmacology, and biophysical characterization of an ERα selective benzothiophene (BTPα) is described. BTPα (4) is a high affinity ligand with 140-fold greater selectivity for ERα (K(i)=0.25 nM) over ERbeta (K(i)=35 nM). In rodent models of estrogen action, BTPα blocks the effects of estrogen in the uterus but mimics the effects estrogen on bone. The basis of ERα selectivity for BTPα was evaluated by using protein crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry. HDX data supports that the n-butyl chain of BTPα stabilizes helix 7 in ERα relative to that of ERβ which we propose leads to an enhancement of affinity to the alpha receptor sub-type.
|
Cytotoxicity against human MCF7 cells after 5 days
|
Homo sapiens
|
794.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Boron-Based 4-Hydroxytamoxifen Bioisosteres for Treatment of de Novo Tamoxifen Resistant Breast Cancer.
Year : 2012
Volume : 3
Issue : 5
First Page : 392
Last Page : 396
Authors : Jiang Q, Zhong Q, Zhang Q, Zheng S, Wang G.
Abstract : Tamoxifen remains the first line therapy for estrogen receptor positive (ER+) breast cancer. However, polymorphisms of the gene encoding P450 2D6 could result in no protein expression or no CYP2D6 enzymatic activity and may significantly reduce the benefit of the hormone therapy. To address this issue, we designed and synthesized three 4-hydroxytamoxifen bioisosteres utilizing a boron-aryl carbon bond that can be oxidized under physiological conditions to yield 4-hydroxytamoxifen. We show that the bioisosteres inhibit the growth of two ER+ breast cancer cell lines, MCF-7 and T47D, with potencies comparable to or greater than that of 4-hydroxytamoxifen. We further demonstrate that after incubation with breast cancer cells, the majority of the bioisosteres has been converted to 4-hydroxytamoxifen. Our study suggests that boron-based 4-hydroxytamoxifen bioisosteres may be an effective therapeutic remedy for intrinsic tamoxifen resistance in breast cancer patients deficient in CYP2D6 metabolism.
|
Antiproliferative activity against human MCF7 cells assessed as inhibition of cell viability at 100 uM after 24 hrs by MTT assay
|
Homo sapiens
|
93.3
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery and structure-activity analysis of selective estrogen receptor modulators via similarity-based virtual screening.
Year : 2012
Volume : 54
First Page : 188
Last Page : 196
Authors : Shen J, Jiang J, Kuang G, Tan C, Liu G, Huang J, Tang Y.
Abstract : A number of selective estrogen receptor modulators (SERMs) were discovered from the SPECS database via a simple protocol. Based on two reference SERMs we identified via structure-based virtual screening previously, ligand-based similarity search and molecular docking filtering were conducted to identify novel SERMs from SPECS library. Among the 36 purchased compounds, 21 were confirmed to be active by in vitro assays, and 10 showed dual profile properties, namely as antagonists of ERα and agonists of ERβ. The anti-proliferative potency of these ligands was also evaluated against MCF-7 cell lines. Further investigation of the anti-proliferative mechanism of compound 3a suggested that it induced a G1 cell cycle arrest in ERα positive MCF-7 cell through ERα mediated cyclin D1 down-regulation.
|
TP_TRANSPORTER: inhibition of Digoxin transepithelial transport (basal to apical)(Digoxin: 5 uM, Tamoxifen: 100 uM) in Caco-2 cells
|
None
|
86.0
%
|
|
Journal : Pharm. Res.
Title : Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein.
Year : 1999
Volume : 16
Issue : 1
First Page : 408
Last Page : 414
Authors : Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, Roden MM, Belas F, Chaudhary AK, Roden DM, Wood AJ, Wilkinson GR.
Abstract : PURPOSE: CYP3A and P-gp both function to reduce the intracellular concentration of drug substrates, one by metabolism and the other by transmembrane efflux. Moreover, it has been serendipitously noted that the two proteins have many common substrates and inhibitors. In order to test this notion more fully, systematic studies were undertaken to determine the P-gp-mediated transport and inhibitory characteristics of prototypical CYP substrates. METHODS: L-MDR1, LLC-PK1, and Caco-2 cells were used to evaluate established CYP substrates as potential P-gp substrates and inhibitors in vitro, and mdr1a deficient mice were used to assess the in vivo relevance of P-gp-mediated transport. RESULTS: Some (terfenadine, erythromycin and lovastatin) but not all (nifedipine and midazolam) CYP3A substrates were found to be P-gp substrates. Except for debrisoquine, none of the prototypical substrates of other common human CYP isoforms were transported by P-gp. Studies in mdr1a disrupted mice confirmed that erythromycin was a P-gp substrate but the CYP3A-inhibitor ketoconazole was not. In addition, CYP3A substrates and inhibitors varied widely in their ability to inhibit the P-gp-mediated transport of digoxin. CONCLUSIONS: These results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
25.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
28.5
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
11.0
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Binding affinity to emopamil binding protein (unknown origin)
|
Homo sapiens
|
2.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of ¹⁸F labeled fluoro-oligo-ethoxylated 4-benzylpiperazine derivatives for sigma-1 receptor imaging.
Year : 2013
Volume : 21
Issue : 1
First Page : 215
Last Page : 222
Authors : Wang X, Li Y, Deuther-Conrad W, Xie F, Chen X, Cui MC, Zhang XJ, Zhang JM, Steinbach J, Brust P, Liu BL, Jia HM.
Abstract : We report the synthesis and evaluation of a series of fluoro-oligo-ethoxylated 4-benzylpiperazine derivatives as potential σ(1) receptor ligands. In vitro competition binding assays showed that 1-(1,3-benzodioxol-5-ylmethyl)-4-(4-(2-fluoroethoxy)benzyl)piperazine (6) exhibits low nanomolar affinity for σ(1) receptors (K(i)=1.85 ± 1.59 nM) and high subtype selectivity (σ(2) receptor: K(i)=291 ± 111 nM; K(i)σ(2)/K(i)σ(1)=157). [(18)F]6 was prepared in 30-50% isolated radiochemical yield, with radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic (18)F(-) substitution of the corresponding tosylate precursor. The logD(pH 7.4) value of [(18)F]6 was found to be 2.57 ± 0.10, which is within the range expected to give high brain uptake. Biodistribution studies in mice demonstrated relatively high concentration of radiotracers in organs known to contain σ(1) receptors, including the brain, lungs, kidneys, heart, and spleen. Administration of haloperidol 5 min prior to injection of [(18)F]6 significantly reduced the concentration of radiotracers in the above-mentioned organs. The accumulation of radiotracers in the bone was quite low suggesting that [(18)F]6 is relatively stable to in vivo defluorination. The ex vivo autoradiography in rat brain showed high accumulation of radiotracers in the brain areas known to possess high expression of σ(1) receptors. These findings suggest that [(18)F]6 is a suitable radiotracer for imaging σ(1) receptors with PET in vivo.
|
Antagonist activity at ERalpha receptor in human MCF7 cells assessed as inhibition of cell growth after 6 days by crystal violet staining method
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel estrogen receptor antagonists using metal-catalyzed coupling reactions and characterization of their biological activity.
Year : 2013
Volume : 56
Issue : 7
First Page : 2779
Last Page : 2790
Authors : Jiang XR, Wang P, Smith CL, Zhu BT.
Abstract : Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer. In this study, we designed and synthesized nine new derivatives of 17β-estradiol (E2) with a bulky side chain attached to its C-7α position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ERα transactivation activity in a luciferase reporter assay and blocked ERα interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ERα-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ERα and showed that they could tightly bind to the ERα in a manner similar to that of ICI-182,780, a pure ER antagonist. These results provide an example that attachment of a bulky side chain to the C-7α position of E2 can produce ER antagonists with ER affinity comparable to that of ICI-182,780.
|
Antagonist activity at Gal4 DBD-fused human ERalpha LBD expressed in HEK293T cells assessed as inhibition of estradiol-induced transcriptional activation after 20 hrs by luciferase reporter gene assay
|
Homo sapiens
|
39.0
nM
|
|
Journal : J. Med. Chem.
Title : Histone deacetylase inhibitors equipped with estrogen receptor modulation activity.
Year : 2013
Volume : 56
Issue : 14
First Page : 5782
Last Page : 5796
Authors : Gryder BE, Rood MK, Johnson KA, Patil V, Raftery ED, Yao LP, Rice M, Azizi B, Doyle DF, Oyelere AK.
Abstract : We describe a set of novel histone deacetylase inhibitors (HDACi) equipped with either an antagonist or an agonist of the estrogen receptor (ER) to confer selective activity against breast cancers. These bifunctional compounds potently inhibit HDAC at nanomolar concentrations and either agonize or antagonize ERα and ERβ. The ER antagonist activities of tamoxifen-HDACi conjugates (Tam-HDACi) are nearly identical to those of tamoxifen. Conversely, ethynyl-estradiol-HDACi conjugates (EED-HDACi) have attenuated ER agonist activities relative to the parent ethynyl-estradiol. In silico docking analysis provides structural basis for the trends of ER agonism/antagonism and ER subtype selectivity. Excitingly, lead Tam-HDACi conjugates show anticancer activity that is selectively more potent against MCF-7 (ERα positive breast cancer) compared to MDA-MB-231 (triple negative breast cancer), DU145 (prostate cancer), or Vero (noncancerous cell line). This dual-targeting approach illustrates the utility of designing small molecules with an emphasis on cell-type selectivity, not merely improved potency, working toward a higher therapeutic index at the earliest stages of drug development.
|
Antiproliferative activity against human MCF7 cells
|
Homo sapiens
|
10.0
ug.mL-1
|
|
Journal : MedChemComm
Title : Recent applications of multicomponent reactions in medicinal chemistry
Year : 2012
Volume : 3
Issue : 10
First Page : 1189
Last Page : 1218
Authors : Slobbe P, Ruijter E, Orru RVA
|
Displacement of fluorescent estrogen from recombinant ERalpha (unknown origin) at 0.1 mg/ml by competition binding assay
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 2,3-diaryl isoquinolinone derivatives as anti-breast cancer agents targeting ERα and VEGFR-2.
Year : 2014
Volume : 24
Issue : 9
First Page : 2129
Last Page : 2133
Authors : Tang Z, Niu S, Liu F, Lao K, Miao J, Ji J, Wang X, Yan M, Zhang L, You Q, Xiao H, Xiang H.
Abstract : The estrogen receptor α is recognized as important pharmaceutical target for breast cancer therapy, and vascular endothelial growth factor receptors (VEGFRs) play important roles in tumor angiogenesis including breast cancer. A series of 2,3-diaryl isoquinolinone derivatives were designed and synthesized targeting both estrogen receptor α (ERα) and VEGFR-2. Bioactivity evaluation showed that compounds 7c, 7d and 7f exhibited significant anti-proliferative and anti-angiogenesis activities via ERα and VEGFR-2 dependent mechanisms.
|
Displacement of fluorescein-labeled estrogen from human recombinant ERalpha by fluorescence polarization based competitive binding affinity assay
|
Homo sapiens
|
61.0
nM
|
|
Journal : J. Med. Chem.
Title : β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand.
Year : 2014
Volume : 57
Issue : 22
First Page : 9370
Last Page : 9382
Authors : O'Boyle NM, Pollock JK, Carr M, Knox AJ, Nathwani SM, Wang S, Caboni L, Zisterer DM, Meegan MJ.
Abstract : Twelve novel β-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM, respectively) and ERβ (IC50 values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and β-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.
|
Displacement of fluorescein-labeled estrogen from human recombinant ERbeta by fluorescence polarization based competitive binding affinity assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand.
Year : 2014
Volume : 57
Issue : 22
First Page : 9370
Last Page : 9382
Authors : O'Boyle NM, Pollock JK, Carr M, Knox AJ, Nathwani SM, Wang S, Caboni L, Zisterer DM, Meegan MJ.
Abstract : Twelve novel β-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM, respectively) and ERβ (IC50 values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and β-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.
|
Binding affinity to human ERalpha
|
Homo sapiens
|
60.9
nM
|
|
Journal : J. Med. Chem.
Title : β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand.
Year : 2014
Volume : 57
Issue : 22
First Page : 9370
Last Page : 9382
Authors : O'Boyle NM, Pollock JK, Carr M, Knox AJ, Nathwani SM, Wang S, Caboni L, Zisterer DM, Meegan MJ.
Abstract : Twelve novel β-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM, respectively) and ERβ (IC50 values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and β-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.
|
Binding affinity to human ERbeta
|
Homo sapiens
|
188.0
nM
|
|
Journal : J. Med. Chem.
Title : β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand.
Year : 2014
Volume : 57
Issue : 22
First Page : 9370
Last Page : 9382
Authors : O'Boyle NM, Pollock JK, Carr M, Knox AJ, Nathwani SM, Wang S, Caboni L, Zisterer DM, Meegan MJ.
Abstract : Twelve novel β-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM, respectively) and ERβ (IC50 values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and β-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.
|
Cytotoxicity against human MCF7 cells after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
8.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Part I. Synthesis, biological evaluation and docking studies of new 2-furylbenzimidazoles as antiangiogenic agents.
Year : 2014
Volume : 87
First Page : 868
Last Page : 880
Authors : Temirak A, Shaker YM, Ragab FA, Ali MM, Ali HI, El Diwani HI.
Abstract : 2-(2-Furyl)-1H-benzimidazoles 3-11 were synthesized and tested for their in vitro VEGF inhibition in MCF-7 cancer cell line. Compound 5a was more potent than Tamoxifen, and compounds 3b, 5a, 5c, 6b, 7a and 10 showed promising potency. Furthermore, compounds (6b, 7a and 10) showed remarkable selective inhibition of COX-2 enzyme close to that of Celecoxcib. Additionally, docking studies were performed using AutoDock 4.2 into the VEGFR2 kinase. Significant correlation exists between the biological activity (IC50 and %VEGF inhibition) against MCF-7 cell line and the molecular docking results (Ki and ΔGb) with correlation coefficients (R(2)) of 0.5513 and 0.4623 respectively. Accordingly, most of the synthesized 2-(2-furyl)-1H-benzimidazoles showed strong antiangiogenic activity against VEGFR2 kinase.
|
Inhibition of VEGF production in human MCF7 cells at cytotoxic IC50 level after 24 hrs by ELISA
|
Homo sapiens
|
98.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Part I. Synthesis, biological evaluation and docking studies of new 2-furylbenzimidazoles as antiangiogenic agents.
Year : 2014
Volume : 87
First Page : 868
Last Page : 880
Authors : Temirak A, Shaker YM, Ragab FA, Ali MM, Ali HI, El Diwani HI.
Abstract : 2-(2-Furyl)-1H-benzimidazoles 3-11 were synthesized and tested for their in vitro VEGF inhibition in MCF-7 cancer cell line. Compound 5a was more potent than Tamoxifen, and compounds 3b, 5a, 5c, 6b, 7a and 10 showed promising potency. Furthermore, compounds (6b, 7a and 10) showed remarkable selective inhibition of COX-2 enzyme close to that of Celecoxcib. Additionally, docking studies were performed using AutoDock 4.2 into the VEGFR2 kinase. Significant correlation exists between the biological activity (IC50 and %VEGF inhibition) against MCF-7 cell line and the molecular docking results (Ki and ΔGb) with correlation coefficients (R(2)) of 0.5513 and 0.4623 respectively. Accordingly, most of the synthesized 2-(2-furyl)-1H-benzimidazoles showed strong antiangiogenic activity against VEGFR2 kinase.
|
Inhibition of human OATP1B1-mediated [3H]estrone 3-sulfate at 100 uM after 5 mins relative to control
|
Homo sapiens
|
16.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : Interaction of human organic anion transporter polypeptides 1B1 and 1B3 with antineoplastic compounds.
Year : 2015
Volume : 92
First Page : 723
Last Page : 731
Authors : Marada VV, Flörl S, Kühne A, Burckhardt G, Hagos Y.
Abstract : Antineoplastic compounds are used in the treatment of a variety of cancers. The effectiveness of an antineoplastic compound to exert its activity is largely dependent on transport proteins involved in the entry of the compound into the cells, and those which drive it out of the cell. Organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), belonging to the SLCO family of proteins, are specifically expressed in the sinusoidal membranes of the liver, and are known to interact with a variety of drugs. The present study deals with the interaction of these proteins with antineoplastic compounds routinely used in cancer chemotherapy. The proteins OATP1B1 and OATP1B3 were functionally characterized in stably transfected human embryonic kidney cells using [(3)H] labeled estrone 3-sulfate and [(3)H] labeled cholecystokinin octapeptide (CCK-8) as substrates, respectively. Substrate uptake experiments performed in the presence of antineoplastic compounds showed that vinblastine and paclitaxel strongly interacted with the OATP1B1 with Ki values of 10.2 μM and 0.84 μM, respectively. OATP1B3 showed highly significant interactions with a variety of antineoplastic compounds including chlorambucil, mitoxantrone, vinblastine, vincristine, paclitaxel and etoposide, with Ki values of 40.6 μM, 3.2 μM, 15.9 μM, 30.6 μM, 1.8 μM and 13.5 μM, respectively. We report several novel interactions of the transporter proteins OATP1B1 and OATP1B3 highlighting the need to investigate their role in drug-drug interactions and cancer chemotherapy.
|
Inhibition of human OATP1B3-mediated [3H]CCK-8 at 100 uM after 5 mins relative to control
|
Homo sapiens
|
38.1
%
|
|
Journal : Eur. J. Med. Chem.
Title : Interaction of human organic anion transporter polypeptides 1B1 and 1B3 with antineoplastic compounds.
Year : 2015
Volume : 92
First Page : 723
Last Page : 731
Authors : Marada VV, Flörl S, Kühne A, Burckhardt G, Hagos Y.
Abstract : Antineoplastic compounds are used in the treatment of a variety of cancers. The effectiveness of an antineoplastic compound to exert its activity is largely dependent on transport proteins involved in the entry of the compound into the cells, and those which drive it out of the cell. Organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), belonging to the SLCO family of proteins, are specifically expressed in the sinusoidal membranes of the liver, and are known to interact with a variety of drugs. The present study deals with the interaction of these proteins with antineoplastic compounds routinely used in cancer chemotherapy. The proteins OATP1B1 and OATP1B3 were functionally characterized in stably transfected human embryonic kidney cells using [(3)H] labeled estrone 3-sulfate and [(3)H] labeled cholecystokinin octapeptide (CCK-8) as substrates, respectively. Substrate uptake experiments performed in the presence of antineoplastic compounds showed that vinblastine and paclitaxel strongly interacted with the OATP1B1 with Ki values of 10.2 μM and 0.84 μM, respectively. OATP1B3 showed highly significant interactions with a variety of antineoplastic compounds including chlorambucil, mitoxantrone, vinblastine, vincristine, paclitaxel and etoposide, with Ki values of 40.6 μM, 3.2 μM, 15.9 μM, 30.6 μM, 1.8 μM and 13.5 μM, respectively. We report several novel interactions of the transporter proteins OATP1B1 and OATP1B3 highlighting the need to investigate their role in drug-drug interactions and cancer chemotherapy.
|
Time dependent inhibition of CYP1A2 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2B6 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C9 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C19 in human liver microsomes at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2D6 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP3A4 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C8 (unknown origin) at 10 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Binding affinity to ERalpha receptor (unknown origin)
|
Homo sapiens
|
24.55
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
Year : 2015
Volume : 58
Issue : 20
First Page : 8128
Last Page : 8140
Authors : De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z.
Abstract : The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
|
Antagonist activity at progesterone receptor in human MCF cells assessed as estradiol-induced receptor response
|
Homo sapiens
|
128.82
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
Year : 2015
Volume : 58
Issue : 20
First Page : 8128
Last Page : 8140
Authors : De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z.
Abstract : The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
|
Antiproliferative activity against human MCF7 cells
|
Homo sapiens
|
57.54
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
Year : 2015
Volume : 58
Issue : 20
First Page : 8128
Last Page : 8140
Authors : De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z.
Abstract : The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
|
Antiproliferative activity against human GBM1 cells assessed as reduction in cell viability at 10 uM incubated for 72 hrs by WST-1 method
|
Homo sapiens
|
98.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).
Year : 2015
Volume : 103
First Page : 210
Last Page : 222
Authors : Elkamhawy A, Viswanath AN, Pae AN, Kim HY, Heo JC, Park WK, Lee CO, Yang H, Kim KH, Nam DH, Seol HJ, Cho H, Roh EJ.
Abstract : Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM.
|
Antiproliferative activity against human GBM2 cells assessed as reduction in cell viability at 10 uM incubated for 72 hrs by WST-1 method
|
Homo sapiens
|
100.8
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).
Year : 2015
Volume : 103
First Page : 210
Last Page : 222
Authors : Elkamhawy A, Viswanath AN, Pae AN, Kim HY, Heo JC, Park WK, Lee CO, Yang H, Kim KH, Nam DH, Seol HJ, Cho H, Roh EJ.
Abstract : Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM.
|
Antiproliferative activity against human GBM3 cells assessed as reduction in cell viability at 10 uM incubated for 72 hrs by WST-1 method
|
Homo sapiens
|
95.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).
Year : 2015
Volume : 103
First Page : 210
Last Page : 222
Authors : Elkamhawy A, Viswanath AN, Pae AN, Kim HY, Heo JC, Park WK, Lee CO, Yang H, Kim KH, Nam DH, Seol HJ, Cho H, Roh EJ.
Abstract : Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM.
|
Displacement of [3H]-E2 from human ER-alpha incubated for 16 to 20 hrs by liquid scintillation counting analysis
|
Homo sapiens
|
8.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel tamoxifen analogues that avoid CYP2D6 metabolism.
Year : 2016
Volume : 112
First Page : 171
Last Page : 179
Authors : Ahmed NS, Elghazawy NH, ElHady AK, Engel M, Hartmann RW, Abadi AH.
Abstract : Tamoxifen (TAM) is a widely used drug in the prophylaxis and treatment of breast cancer. TAM is metabolized to the more active 4-hydroxytamoxifen (4-OH-TAM) and endoxifen by cytochrome P450 (CYP) mainly CYP2D6 and CYP3A4 enzymes. Due to the genetic polymorphisms in CYP2D6 genes, high variation in the clinical outcomes of TAM treatment is observed among women of different populations. To address this issue, novel TAM analogues with possible altered activation pathways were synthesized. These analogues were tested for their antiproliferative action on MCF-7 breast cancer cell lines as well as their binding affinity for estrogen receptor (ER) ER-α and ER-β receptors. These entire novel compounds showed better antiproliferative activity than did TAM on the MCF-7 cells. Moreover, compound 10 exhibited a half maximal growth inhibition (GI50) that was 1000 times more potent than that of TAM (GI50 < 0.005 μM vs 1.58 μM, respectively). Along with a broad spectrum activity on various cancer cell lines, all the TAM analogues showed considerable activity on the ER-negative breast cancer cell line. For further study, compound 10 was incubated in human liver microsomes (HLM), human hepatocytes (hHEP) and CYP2D6 supersomes. The active hydroxyl metabolite was detected after incubation in HLM and hHEP, implicating the involvement of other enzymes in its metabolism. These results prove that this novel series of TAM analogues might provide improved clinical outcomes for poor 2D6 metabolizers.
|
Displacement of [3H]-E2 from human ER-beta incubated for 16 to 20 hrs by liquid scintillation counting analysis
|
Homo sapiens
|
180.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel tamoxifen analogues that avoid CYP2D6 metabolism.
Year : 2016
Volume : 112
First Page : 171
Last Page : 179
Authors : Ahmed NS, Elghazawy NH, ElHady AK, Engel M, Hartmann RW, Abadi AH.
Abstract : Tamoxifen (TAM) is a widely used drug in the prophylaxis and treatment of breast cancer. TAM is metabolized to the more active 4-hydroxytamoxifen (4-OH-TAM) and endoxifen by cytochrome P450 (CYP) mainly CYP2D6 and CYP3A4 enzymes. Due to the genetic polymorphisms in CYP2D6 genes, high variation in the clinical outcomes of TAM treatment is observed among women of different populations. To address this issue, novel TAM analogues with possible altered activation pathways were synthesized. These analogues were tested for their antiproliferative action on MCF-7 breast cancer cell lines as well as their binding affinity for estrogen receptor (ER) ER-α and ER-β receptors. These entire novel compounds showed better antiproliferative activity than did TAM on the MCF-7 cells. Moreover, compound 10 exhibited a half maximal growth inhibition (GI50) that was 1000 times more potent than that of TAM (GI50 < 0.005 μM vs 1.58 μM, respectively). Along with a broad spectrum activity on various cancer cell lines, all the TAM analogues showed considerable activity on the ER-negative breast cancer cell line. For further study, compound 10 was incubated in human liver microsomes (HLM), human hepatocytes (hHEP) and CYP2D6 supersomes. The active hydroxyl metabolite was detected after incubation in HLM and hHEP, implicating the involvement of other enzymes in its metabolism. These results prove that this novel series of TAM analogues might provide improved clinical outcomes for poor 2D6 metabolizers.
|
Antiestrogenic activity at ER-alpha in human MCF7 cells assessed as inhibition of E2-induced progesterone receptor mRNA expression at 1 uM by RT-PCR method relative to control
|
Homo sapiens
|
70.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and evaluation of 6-aryl-indenoisoquinolone derivatives dual targeting ERα and VEGFR-2 as anti-breast cancer agents.
Year : 2016
Volume : 118
First Page : 328
Last Page : 339
Authors : Tang Z, Wu C, Wang T, Lao K, Wang Y, Liu L, Muyaba M, Xu P, He C, Luo G, Qian Z, Niu S, Wang L, Wang Y, Xiao H, You Q, Xiang H.
Abstract : The estrogen receptors have played important roles in breast cancer development and progression. Selective estrogen receptor modulators, such as Tamoxifen, have showed great benefits in the treatment and prevention of breast cancer. But the disadvantages of induction of endometrial cancer and drug resistance have limited their use. Multiple ligand which act at multiple biomolecular targets may exert favorable advantages of improved efficacy with lower incidence of side effects. In this work, we described the synthesis and evaluation of a series of 6-aryl-indenoisoquinolone derivatives as dual ERα and VEGFR-2 inhibitors. These compounds presented good ERα binding affinity and ERα antagonistic activity, as well as potent VEGFR-2 inhibitory potency. They also possessed excellent anti-proliferative activities against MCF-7, MDA-MB-231, Ishikawa and HUVEC cell lines. Further investigation of selective compound 21c showed that it was able to inhibit the activation of VEGFR-2 and the signaling transduction of Raf-1/MAPK/ERK pathway in MCF-7 cells.
|
Inhibition of PKC in human SH-SY5Y cells assessed as inhibition of PMA-stimulated MARCKS phosphorylation at 3 uM preincubated for 1 hr followed by PMA-stimulation for 15 mins by Western blot analysis relative to control
|
Homo sapiens
|
27.0
%
|
|
Journal : Bioorg Med Chem
Title : Design and synthesis of triarylacrylonitrile analogues of tamoxifen with improved binding selectivity to protein kinase C.
Year : 2016
Volume : 24
Issue : 21
First Page : 5495
Last Page : 5504
Authors : Carpenter C, Sorenson RJ, Jin Y, Klossowski S, Cierpicki T, Gnegy M, Showalter HD.
Abstract : The clinical selective estrogen receptor modulator tamoxifen is also a modest inhibitor of protein kinase C, a target implicated in several untreatable brain diseases such as amphetamine abuse. This inhibition and tamoxifen's ability to cross the blood brain barrier make it an attractive scaffold to conduct further SAR studies toward uncovering effective therapies for such diseases. Utilizing the known compound 6a as a starting template and guided by computational tools to derive physicochemical properties known to be important for CNS permeable drugs, the design and synthesis of a small series of novel triarylacrylonitrile analogues have been carried out providing compounds with enhanced potency and selectivity for PKC over the estrogen receptor relative to tamoxifen. Shortened synthetic routes compared to classical procedures have been developed for analogues incorporating a β-phenyl ring, which involve installing dialkylaminoalkoxy side chains first off the α and/or α' rings of a precursor benzophenone and then condensing the resultant ketones with phenylacetonitrile anion. A second novel, efficient and versatile route utilizing Suzuki chemistry has also been developed, which will allow for the introduction of a wide range of β-aryl or β-heteroaryl moieties and side-chain substituents onto the acrylonitrile core. For analogues possessing a single side chain off the α- or α'-ring, novel 2D NMR experiments have been carried out that allow for unambiguous assignment of E- and Z-stereochemistry. From the SAR analysis, one compound, 6c, shows markedly increased potency and selectivity for inhibiting PKC with an IC50 of 80nM for inhibition of PKC protein substrate and >10μM for binding to the estrogen receptor α (tamoxifen IC50=20μM and 222nM, respectively). The data on 6c provide support for further exploration of PKC as a druggable target for the treatment of amphetamine abuse.
|
Inhibition of PKC in human SH-SY5Y cells assessed as inhibition of PMA-stimulated MARCKS phosphorylation at 10 uM preincubated for 1 hr followed by PMA-stimulation for 15 mins by Western blot analysis relative to control
|
Homo sapiens
|
52.0
%
|
|
Journal : Bioorg Med Chem
Title : Design and synthesis of triarylacrylonitrile analogues of tamoxifen with improved binding selectivity to protein kinase C.
Year : 2016
Volume : 24
Issue : 21
First Page : 5495
Last Page : 5504
Authors : Carpenter C, Sorenson RJ, Jin Y, Klossowski S, Cierpicki T, Gnegy M, Showalter HD.
Abstract : The clinical selective estrogen receptor modulator tamoxifen is also a modest inhibitor of protein kinase C, a target implicated in several untreatable brain diseases such as amphetamine abuse. This inhibition and tamoxifen's ability to cross the blood brain barrier make it an attractive scaffold to conduct further SAR studies toward uncovering effective therapies for such diseases. Utilizing the known compound 6a as a starting template and guided by computational tools to derive physicochemical properties known to be important for CNS permeable drugs, the design and synthesis of a small series of novel triarylacrylonitrile analogues have been carried out providing compounds with enhanced potency and selectivity for PKC over the estrogen receptor relative to tamoxifen. Shortened synthetic routes compared to classical procedures have been developed for analogues incorporating a β-phenyl ring, which involve installing dialkylaminoalkoxy side chains first off the α and/or α' rings of a precursor benzophenone and then condensing the resultant ketones with phenylacetonitrile anion. A second novel, efficient and versatile route utilizing Suzuki chemistry has also been developed, which will allow for the introduction of a wide range of β-aryl or β-heteroaryl moieties and side-chain substituents onto the acrylonitrile core. For analogues possessing a single side chain off the α- or α'-ring, novel 2D NMR experiments have been carried out that allow for unambiguous assignment of E- and Z-stereochemistry. From the SAR analysis, one compound, 6c, shows markedly increased potency and selectivity for inhibiting PKC with an IC50 of 80nM for inhibition of PKC protein substrate and >10μM for binding to the estrogen receptor α (tamoxifen IC50=20μM and 222nM, respectively). The data on 6c provide support for further exploration of PKC as a druggable target for the treatment of amphetamine abuse.
|
Displacement of Fluormone ES2 Green from human recombinant full length ERalpha expressed in insect cells measured up to 4 hrs by fluorescence polarization assay
|
Homo sapiens
|
222.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design and synthesis of triarylacrylonitrile analogues of tamoxifen with improved binding selectivity to protein kinase C.
Year : 2016
Volume : 24
Issue : 21
First Page : 5495
Last Page : 5504
Authors : Carpenter C, Sorenson RJ, Jin Y, Klossowski S, Cierpicki T, Gnegy M, Showalter HD.
Abstract : The clinical selective estrogen receptor modulator tamoxifen is also a modest inhibitor of protein kinase C, a target implicated in several untreatable brain diseases such as amphetamine abuse. This inhibition and tamoxifen's ability to cross the blood brain barrier make it an attractive scaffold to conduct further SAR studies toward uncovering effective therapies for such diseases. Utilizing the known compound 6a as a starting template and guided by computational tools to derive physicochemical properties known to be important for CNS permeable drugs, the design and synthesis of a small series of novel triarylacrylonitrile analogues have been carried out providing compounds with enhanced potency and selectivity for PKC over the estrogen receptor relative to tamoxifen. Shortened synthetic routes compared to classical procedures have been developed for analogues incorporating a β-phenyl ring, which involve installing dialkylaminoalkoxy side chains first off the α and/or α' rings of a precursor benzophenone and then condensing the resultant ketones with phenylacetonitrile anion. A second novel, efficient and versatile route utilizing Suzuki chemistry has also been developed, which will allow for the introduction of a wide range of β-aryl or β-heteroaryl moieties and side-chain substituents onto the acrylonitrile core. For analogues possessing a single side chain off the α- or α'-ring, novel 2D NMR experiments have been carried out that allow for unambiguous assignment of E- and Z-stereochemistry. From the SAR analysis, one compound, 6c, shows markedly increased potency and selectivity for inhibiting PKC with an IC50 of 80nM for inhibition of PKC protein substrate and >10μM for binding to the estrogen receptor α (tamoxifen IC50=20μM and 222nM, respectively). The data on 6c provide support for further exploration of PKC as a druggable target for the treatment of amphetamine abuse.
|
Displacement of [3H]E2 from GST-fused ERalpha-LBD (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by liquid scintillation counting method
|
Homo sapiens
|
226.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents.
Year : 2017
Volume : 25
Issue : 20
First Page : 5216
Last Page : 5237
Authors : Torikai K, Koga R, Liu X, Umehara K, Kitano T, Watanabe K, Oishi T, Noguchi H, Shimohigashi Y.
Abstract : Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC50 < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).
|
Displacement of [3H]E2 from GST-fused ERbeta-LBD (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by liquid scintillation counting method
|
Homo sapiens
|
79.7
nM
|
|
Journal : Bioorg Med Chem
Title : Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents.
Year : 2017
Volume : 25
Issue : 20
First Page : 5216
Last Page : 5237
Authors : Torikai K, Koga R, Liu X, Umehara K, Kitano T, Watanabe K, Oishi T, Noguchi H, Shimohigashi Y.
Abstract : Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC50 < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).
|
Binding affinity to human ERRgamma
|
Homo sapiens
|
62.2
nM
|
|
Journal : Bioorg Med Chem
Title : Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents.
Year : 2017
Volume : 25
Issue : 20
First Page : 5216
Last Page : 5237
Authors : Torikai K, Koga R, Liu X, Umehara K, Kitano T, Watanabe K, Oishi T, Noguchi H, Shimohigashi Y.
Abstract : Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC50 < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).
|
Antagonist activity at full length ERalpha (unknown origin) expressed in human HeLa cells incubated for 24 hrs by ERE-driven luciferase reporter gene assay
|
Homo sapiens
|
341.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents.
Year : 2017
Volume : 25
Issue : 20
First Page : 5216
Last Page : 5237
Authors : Torikai K, Koga R, Liu X, Umehara K, Kitano T, Watanabe K, Oishi T, Noguchi H, Shimohigashi Y.
Abstract : Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC50 < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).
|
Inhibition of Ebolavirus glycoprotein/matrix protein VP40 entry in human HeLa cells after 4.5 hrs beta-lactamase reporter assay
|
Ebolavirus
|
730.0
nM
|
|
Journal : J Med Chem
Title : Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors.
Year : 2018
Volume : 61
Issue : 8
First Page : 3582
Last Page : 3594
Authors : Capuzzi SJ, Sun W, Muratov EN, Martínez-Romero C, He S, Zhu W, Li H, Tawa G, Fisher EG, Xu M, Shinn P, Qiu X, García-Sastre A, Zheng W, Tropsha A.
Abstract : The Ebola virus (EBOV) causes severe human infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry into human cells. Using data from this screen, quantitative structure-activity relationship models were built and employed for virtual screening of a ∼17 million compound library. Experimental testing of 102 hits yielded 14 compounds with IC50 values under 10 μM, including several sub-micromolar inhibitors, and more than 10-fold selectivity against host cytotoxicity. These confirmed hits include FDA-approved drugs and clinical candidates with non-antiviral indications, as well as compounds with novel scaffolds and no previously known bioactivity. Five selected hits inhibited BSL-4 live-EBOV infection in a dose-dependent manner, including vindesine (0.34 μM). Additional studies of these novel anti-EBOV compounds revealed their mechanisms of action, including the inhibition of NPC1 protein, cathepsin B/L, and lysosomal function. Compounds identified in this study are among the most potent and well-characterized anti-EBOV inhibitors reported to date.
|
Inhibition of fluorescent estrogen binding to full length untagged human ERalpha expressed in insect cells at 10 uM after 2 hrs by fluorescent polarization assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2-methoxyestradiol analogs as dual selective estrogen receptor modulators (SERMs) and antiangiogenic agents.
Year : 2017
Volume : 139
First Page : 390
Last Page : 400
Authors : Lao K, Wang Y, Chen M, Zhang J, You Q, Xiang H.
Abstract : 2-methoxyestradiol is a novel agent showing both anti-angiogenic and vascular disrupting properties. In this study, a series of 11α-substituted 2-methoxyestradiol analogs have been designed and synthesized targeting dual ERα and microtubulin. Biological evaluation was performed on their anti-proliferative activities against 5 different cell lines. The results indicated that most compounds exhibited good activities, in which compound 24c and 30c showed the best activity with low micromolar IC50 (2.73 μM -7.75 μM) in all cell lines. The investigation of ER affinity showed that the majority of the compounds displayed good activity at the concentration of 50 μM. In further mechanism study, it was observed that 24c and 30c could induce G2/M cell cycle arrest as well as significant anti-estrogenic activity. In CAM assay, compound 24c and 30c presented significantly anti-angiogenesis activity comparable with 2-methoxyestradiol. Overall, based on biological activities data, 24c and 30c can be identified as a potential lead molecule which might be of therapeutic importance for cancer treatment.
|
Inhibition of estrogen receptor in human MCF7 cells assessed as inhibition of estradiol-induced PgR mRNA expression at 2 uM by RT-PCR method relative to control
|
Homo sapiens
|
80.0
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2-methoxyestradiol analogs as dual selective estrogen receptor modulators (SERMs) and antiangiogenic agents.
Year : 2017
Volume : 139
First Page : 390
Last Page : 400
Authors : Lao K, Wang Y, Chen M, Zhang J, You Q, Xiang H.
Abstract : 2-methoxyestradiol is a novel agent showing both anti-angiogenic and vascular disrupting properties. In this study, a series of 11α-substituted 2-methoxyestradiol analogs have been designed and synthesized targeting dual ERα and microtubulin. Biological evaluation was performed on their anti-proliferative activities against 5 different cell lines. The results indicated that most compounds exhibited good activities, in which compound 24c and 30c showed the best activity with low micromolar IC50 (2.73 μM -7.75 μM) in all cell lines. The investigation of ER affinity showed that the majority of the compounds displayed good activity at the concentration of 50 μM. In further mechanism study, it was observed that 24c and 30c could induce G2/M cell cycle arrest as well as significant anti-estrogenic activity. In CAM assay, compound 24c and 30c presented significantly anti-angiogenesis activity comparable with 2-methoxyestradiol. Overall, based on biological activities data, 24c and 30c can be identified as a potential lead molecule which might be of therapeutic importance for cancer treatment.
|
Displacement of fluorescent estrogen ligand from recombinant human ERalpha expressed in insect cells at 10 uM incubated for 2 hrs by polarization
|
Homo sapiens
|
94.79
%
|
|
Journal : Eur J Med Chem
Title : Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ERα/VEGFR-2 ligands for treatment of breast cancer.
Year : 2017
Volume : 140
First Page : 252
Last Page : 273
Authors : Luo G, Li X, Zhang G, Wu C, Tang Z, Liu L, You Q, Xiang H.
Abstract : There is considerable interest in developing new SERMs as multifunctional agents in women's health. Development of dual selective estrogen receptor modulators/VEGFR-2 inhibitors (SERMs/V-2I) has been an attractive strategy for the discovery of new breast cancer therapeutic agents. Our previous efforts led to the preparation of a series of 3-aryl-4-anilino-2H-chromen-2-ones endowed with potent estrogen receptor binding affinity and anti-proliferative efficacy. In this study, various structurally related 3-aryl-4-anilino/aryloxy-2H-chromen-2-one analogues were rationally designed, synthesized and evaluated as a new chemo-type of dual ERα and VEGFR-2 inhibitors. Most of the derivatives exhibited potent activities in both enzymatic and cellular assays. SAR investigation revealed that introducing of bioisosteric O atom at the C-4 position of coumarin scaffold is beneficial to improve the inhibitory potency, especially in ERα binding affinity assay. Furthermore, most of the piperidyl substituted compounds showed better inhibitory activity against MCF-7 and Ishikawa cells than lead compounds BL-18d, tamoxifen and Vandetanib. Optimization of the hit compound, identified in an ERα binding affinity assay, led to compound 42d, exhibiting an IC50 for ERα binding affinity of 2.19 μM while retaining an excellent inhibition on VGFR-2 as well as a potent suppression on the growth of angiogenesis-related cells. In RT-PCR assay, 42d exerted significantly antiestrogenic property via suppressing the expression of progesterone receptor (PgR) mRNA in MCF-7 cells, which was consistent with the ERα antagonistic property of a selective estrogen receptor modulator. Further mechanism investigation demonstrated that compound 42d could inhibit the activation of VEGFR-2 and subsequent signaling transduction of Raf-1/MAPK/ERK pathway in MCF-7 cells. All these results together with molecular modeling studies open a new avenue for the development of multifunctional agents targeting ERα and VEGFR-2 in the therapy of some breast cancers.
|
Inhibition of VEGFR2 protein expression in human MCF7 cells at cytotoxic IC50 after 24 hrs by ELISA relative to untreated control
|
Homo sapiens
|
98.0
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors.
Year : 2017
Volume : 136
First Page : 315
Last Page : 329
Authors : Abdullaziz MA, Abdel-Mohsen HT, El Kerdawy AM, Ragab FAF, Ali MM, Abu-Bakr SM, Girgis AS, El Diwani HI.
Abstract : Inhibition of angiogenesis through inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) has been applied in cancer therapy because of its important role in promoting cancer growth and metastasis. In the presented study, a series of benzimidazol-furan hybrids was designed and synthesized through facile synthetic pathways. Evaluation of the synthesized compounds for their in vitro cytotoxic activity against breast (MCF-7) and hepatocellular (HepG2) carcinoma cell lines was performed. Two of the synthesized conjugates, 10b and 15, showed potent antiproliferative properties against MCF-7 cell line (IC50 = 21.25, 21.35 μM, respectively) in comparison to tamoxifen (IC50 = 21.57 μM). Additionally, compounds 10a, 10b, 15 and 17 showed promising potency (IC50 = 25.95, 22.58, 26.94 and 31.06 μM, respectively) against liver carcinoma cell line HepG2 in contrast to cisplatin (IC50 = 31.16 μM). Moreover, in vitro evaluation of the synthesized compounds for their effect on the level of VEGFR-2 in MCF-7 cell line showed their potent inhibitory activity relative to control untreated cells. Four compounds 10a, 10b, 14 and 15 showed 92-96% reduction in VEGFR-2 level, compared with tamoxifen and sorafenib which showed inhibition percentage of 98% and 95.75%, respectively. Compound 10a was found to have promising VEGFR-2 inhibitory activity (IC50 = 0.64 μM) in comparison to sorafenib (IC50 = 0.1 μM). Molecular docking was performed to study the binding pattern of the newly synthesized compounds with VEGFR-2 active site. Molecular docking attributed their good VEGFR-2 inhibitory activity to their hydrogen bonding interaction with the key amino acids in VEGFR-2 active site, Glu885 and Asp1046, and their hydrophobic interaction by their 2-furylbenzimidazole moiety with the allosteric hydrophobic back pocket in a type III inhibitors-like binding mode. The binding interaction is augmented by a ring substituent with long chain extension at position 1 of the benzimidazole due to its hydrophobic interaction with the hydrophobic side chains of the amino acids at the interface between the ATP binding site and the allosteric back pocket. Structure-activity relationship (SAR) was inferred for future optimization based on the performed biological and docking studies.
|
Reduction in uterine wet weight in ethynyl estradiol-stimulated CD-IGS rat at 60 mg/kg, po dosed daily for 3 days by gavage followed 15 mins later by 0.1 mg/kg, po ethynyl estradiol and measured 24 hrs after last dose by immature rat uterine wet weight assay
|
Rattus norvegicus
|
78.0
%
|
|
Journal : J Med Chem
Title : Identification of an Orally Bioavailable Chromene-Based Selective Estrogen Receptor Degrader (SERD) That Demonstrates Robust Activity in a Model of Tamoxifen-Resistant Breast Cancer.
Year : 2018
Volume : 61
Issue : 17
First Page : 7917
Last Page : 7928
Authors : Nagasawa J, Govek S, Kahraman M, Lai A, Bonnefous C, Douglas K, Sensintaffar J, Lu N, Lee K, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Joseph JD, Darimont B, Brigham D, Maheu K, Heyman R, Rix PJ, Hager JH, Smith ND.
Abstract : About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.
|
Inhibition of estradiol-induced proliferation in human Ishikawa cells after 72 hrs by Cell-titer-Glo assay
|
Homo sapiens
|
7.87
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Functional evaluation of synthetic flavonoids and chalcones for potential antiviral and anticancer properties.
Year : 2017
Volume : 27
Issue : 11
First Page : 2350
Last Page : 2356
Authors : Mateeva N, Eyunni SVK, Redda KK, Ononuju U, Hansberry TD, Aikens C, Nag A.
Abstract : Flavonoids, stilbenes, and chalcones are plant secondary metabolites that often possess diverse biological activities including anti-inflammatory, anti-cancer, and anti-viral activities. The wide range of bioactivities poses a challenge to identify their targets. Here, we studied a set of synthetically generated flavonoids and chalcones to evaluate for their biological activity, and compared similarly substituted flavonoids and chalcones. Substituted chalcones, but not flavonoids, showed inhibition of viral translation without significantly affecting viral replication in cells infected with hepatitis C virus (HCV). We suggest that the chalcones used in this study inhibit mammalian target of rapamycin (mTOR) pathway by ablating phosphorylation of ribosomal protein 6 (rps6), and also the kinase necessary for phosphorylating rps6 in Huh7.5 cells (pS6K1). In addition, selected chalcones showed inhibition of growth in Ishikawa, MCF7, and MDA-MB-231 cells resulting an IC50 of 1-6µg/mL. When similarly substituted flavonoids were used against the same set of cancer cells, we did not observe any inhibitory effect. Together, we report that chalcones show potential for anti-viral and anti-cancer activities compared to similarly substituted flavonoids.
|
Inhibition of estradiol-induced proliferation in human MCF7 cells after 72 hrs by Cell-titer-Glo assay
|
Homo sapiens
|
3.99
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Functional evaluation of synthetic flavonoids and chalcones for potential antiviral and anticancer properties.
Year : 2017
Volume : 27
Issue : 11
First Page : 2350
Last Page : 2356
Authors : Mateeva N, Eyunni SVK, Redda KK, Ononuju U, Hansberry TD, Aikens C, Nag A.
Abstract : Flavonoids, stilbenes, and chalcones are plant secondary metabolites that often possess diverse biological activities including anti-inflammatory, anti-cancer, and anti-viral activities. The wide range of bioactivities poses a challenge to identify their targets. Here, we studied a set of synthetically generated flavonoids and chalcones to evaluate for their biological activity, and compared similarly substituted flavonoids and chalcones. Substituted chalcones, but not flavonoids, showed inhibition of viral translation without significantly affecting viral replication in cells infected with hepatitis C virus (HCV). We suggest that the chalcones used in this study inhibit mammalian target of rapamycin (mTOR) pathway by ablating phosphorylation of ribosomal protein 6 (rps6), and also the kinase necessary for phosphorylating rps6 in Huh7.5 cells (pS6K1). In addition, selected chalcones showed inhibition of growth in Ishikawa, MCF7, and MDA-MB-231 cells resulting an IC50 of 1-6µg/mL. When similarly substituted flavonoids were used against the same set of cancer cells, we did not observe any inhibitory effect. Together, we report that chalcones show potential for anti-viral and anti-cancer activities compared to similarly substituted flavonoids.
|
Inhibition of estradiol-induced proliferation in human MDA-MB-231 cells after 72 hrs by Cell-titer-Glo assay
|
Homo sapiens
|
7.85
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Functional evaluation of synthetic flavonoids and chalcones for potential antiviral and anticancer properties.
Year : 2017
Volume : 27
Issue : 11
First Page : 2350
Last Page : 2356
Authors : Mateeva N, Eyunni SVK, Redda KK, Ononuju U, Hansberry TD, Aikens C, Nag A.
Abstract : Flavonoids, stilbenes, and chalcones are plant secondary metabolites that often possess diverse biological activities including anti-inflammatory, anti-cancer, and anti-viral activities. The wide range of bioactivities poses a challenge to identify their targets. Here, we studied a set of synthetically generated flavonoids and chalcones to evaluate for their biological activity, and compared similarly substituted flavonoids and chalcones. Substituted chalcones, but not flavonoids, showed inhibition of viral translation without significantly affecting viral replication in cells infected with hepatitis C virus (HCV). We suggest that the chalcones used in this study inhibit mammalian target of rapamycin (mTOR) pathway by ablating phosphorylation of ribosomal protein 6 (rps6), and also the kinase necessary for phosphorylating rps6 in Huh7.5 cells (pS6K1). In addition, selected chalcones showed inhibition of growth in Ishikawa, MCF7, and MDA-MB-231 cells resulting an IC50 of 1-6µg/mL. When similarly substituted flavonoids were used against the same set of cancer cells, we did not observe any inhibitory effect. Together, we report that chalcones show potential for anti-viral and anti-cancer activities compared to similarly substituted flavonoids.
|
Displacement of fluorescein-labeled estradiol (fluoromone) from human recombinant full-length estrogen receptor alpha after 2 hrs by fluorescence polarization assay
|
Homo sapiens
|
70.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity.
Year : 2018
Volume : 61
Issue : 2
First Page : 514
Last Page : 534
Authors : O'Boyle NM, Barrett I, Greene LM, Carr M, Fayne D, Twamley B, Knox AJS, Keely NO, Zisterer DM, Meegan MJ.
Abstract : Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized: series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERβ. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.
|
Displacement of fluorescein-labeled estradiol (fluoromone) from human recombinant full-length estrogen receptor beta after 2 hrs by fluorescence polarization assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity.
Year : 2018
Volume : 61
Issue : 2
First Page : 514
Last Page : 534
Authors : O'Boyle NM, Barrett I, Greene LM, Carr M, Fayne D, Twamley B, Knox AJS, Keely NO, Zisterer DM, Meegan MJ.
Abstract : Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized: series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERβ. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.
|
Antagonist activity at estrogen receptor alpha/beta in human Ishikawa cells after 72 hrs by alkaline phosphatase assay
|
Homo sapiens
|
280.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity.
Year : 2018
Volume : 61
Issue : 2
First Page : 514
Last Page : 534
Authors : O'Boyle NM, Barrett I, Greene LM, Carr M, Fayne D, Twamley B, Knox AJS, Keely NO, Zisterer DM, Meegan MJ.
Abstract : Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized: series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERβ. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.
|
Displacement of fluorescein-labeled estradiol (fluoromone) from human recombinant full-length untagged estrogen receptor alpha expressed in Spodoptera frugiperda by fluorescence polarization assay
|
Homo sapiens
|
60.9
nM
|
|
Journal : J Med Chem
Title : Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity.
Year : 2018
Volume : 61
Issue : 2
First Page : 514
Last Page : 534
Authors : O'Boyle NM, Barrett I, Greene LM, Carr M, Fayne D, Twamley B, Knox AJS, Keely NO, Zisterer DM, Meegan MJ.
Abstract : Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized: series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERβ. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.
|
Displacement of fluorescein-labeled estradiol (fluoromone) from human recombinant full-length untagged estrogen receptor beta expressed in insect cells by fluorescence polarization assay
|
Homo sapiens
|
188.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity.
Year : 2018
Volume : 61
Issue : 2
First Page : 514
Last Page : 534
Authors : O'Boyle NM, Barrett I, Greene LM, Carr M, Fayne D, Twamley B, Knox AJS, Keely NO, Zisterer DM, Meegan MJ.
Abstract : Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized: series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERβ. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.
|
Displacement of Fluormone ES2 Green from full length human ER-alpha expressed in insect cells at 10 uM after 2 hrs by fluorescence polarization assay relative to control
|
Homo sapiens
|
92.36
%
|
|
Journal : Eur J Med Chem
Title : Structure-activity relationships of 2, 4-disubstituted pyrimidines as dual ERα/VEGFR-2 ligands with anti-breast cancer activity.
Year : 2018
Volume : 150
First Page : 783
Last Page : 795
Authors : Luo G, Tang Z, Lao K, Li X, You Q, Xiang H.
Abstract : Both ERα and VEGFR-2 are important targets for cancer therapies. Here a series of 2, 4-disubstituted pyrimidine derivatives were designed, synthesized and evaluated as dual ERα/VEGFR-2 ligands. Most of the derivatives exhibited potent activities in both enzymatic and cellular assays. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section is important factors for the enhancement of ERα-binding affinity. The most potent compound II-9OH, an analog of 2-(4-hydroxylphenyl)pyrimidine, was 19-fold more efficacious than tamoxifen in MCF-7 cancer cells and exhibited the best ERα binding affinity (IC50 = 1.64 μM) as well as excellent VEGFR-2 inhibition (IC50 = 0.085 μM). Furthermore, this dual targeted compound II-9OH exerted significantly antiestrogenic property via suppressing the expression of progesterone receptor (PgR) mRNA in MCF-7 cells and also showed obvious in vivo angiogenesis inhibitory effects in CAM assay. An induction of apoptosis and a decrease in cell migration, accompanied by transduction inhibition of Raf-1/MAPK/ERK pathway, were observed in MCF-7 cells after treatment with II-9OH, suggesting that II-9OH is a promising candidate for the development of multifunctional agents targeting ERα and VEGFR-2 in the therapy of some breast cancers.
|
Displacement of [3H]E2 from human recombinant ERalpha assessed as receptor binding after 45 mins by scintillation counting method
|
Homo sapiens
|
100.0
nM
|
|
Journal : Eur J Med Chem
Title : Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives.
Year : 2018
Volume : 143
First Page : 515
Last Page : 531
Authors : Shagufta, Ahmad I.
Abstract : Tamoxifen (ICI 46 474), trans-1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, is the most commonly used drug for the treatment of estrogen receptor positive breast cancer and has been saving lives worldwide for the past four decades. Tamoxifen is considered a pioneering drug due to its ubiquitous use in both treatment and chemoprevention of breast cancer and also for research addressing novel selective estrogen receptor modulators (SERMs). Tamoxifen is cost effective, lifesaving, and devoid of major side effects in the majority of patients. The discovery of tamoxifen metabolites such as 4-hydroxy tamoxifen, N-desmethyl tamoxifen, and endoxifen has facilitated understanding of tamoxifen's and its metabolites' mechanisms of action in breast cancer therapy. Continuous efforts are being made by both industry and academia to synthesize novel tamoxifen derivatives in order to better understand the mechanism of this drug's action and to generate new agents with reduced side effects for many therapeutic targets. This review article comprises the tamoxifen derivatives reported in the literature in the last few years and we anticipate that it will assist medicinal chemists in the synthesis of novel and pharmacologically potent agents for various therapeutic targets.
|
Inhibition of PKC in rat brain soluble fraction at 3 uM using calf thymus H1 histone, phosphatidylserine and [gamma-32P]ATP by liquid scintillation counting method
|
Rattus norvegicus
|
27.0
%
|
|
Journal : Eur J Med Chem
Title : Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives.
Year : 2018
Volume : 143
First Page : 515
Last Page : 531
Authors : Shagufta, Ahmad I.
Abstract : Tamoxifen (ICI 46 474), trans-1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, is the most commonly used drug for the treatment of estrogen receptor positive breast cancer and has been saving lives worldwide for the past four decades. Tamoxifen is considered a pioneering drug due to its ubiquitous use in both treatment and chemoprevention of breast cancer and also for research addressing novel selective estrogen receptor modulators (SERMs). Tamoxifen is cost effective, lifesaving, and devoid of major side effects in the majority of patients. The discovery of tamoxifen metabolites such as 4-hydroxy tamoxifen, N-desmethyl tamoxifen, and endoxifen has facilitated understanding of tamoxifen's and its metabolites' mechanisms of action in breast cancer therapy. Continuous efforts are being made by both industry and academia to synthesize novel tamoxifen derivatives in order to better understand the mechanism of this drug's action and to generate new agents with reduced side effects for many therapeutic targets. This review article comprises the tamoxifen derivatives reported in the literature in the last few years and we anticipate that it will assist medicinal chemists in the synthesis of novel and pharmacologically potent agents for various therapeutic targets.
|
Inhibition of estrogen receptor (unknown origin)
|
Homo sapiens
|
222.0
nM
|
|
Journal : Eur J Med Chem
Title : Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives.
Year : 2018
Volume : 143
First Page : 515
Last Page : 531
Authors : Shagufta, Ahmad I.
Abstract : Tamoxifen (ICI 46 474), trans-1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, is the most commonly used drug for the treatment of estrogen receptor positive breast cancer and has been saving lives worldwide for the past four decades. Tamoxifen is considered a pioneering drug due to its ubiquitous use in both treatment and chemoprevention of breast cancer and also for research addressing novel selective estrogen receptor modulators (SERMs). Tamoxifen is cost effective, lifesaving, and devoid of major side effects in the majority of patients. The discovery of tamoxifen metabolites such as 4-hydroxy tamoxifen, N-desmethyl tamoxifen, and endoxifen has facilitated understanding of tamoxifen's and its metabolites' mechanisms of action in breast cancer therapy. Continuous efforts are being made by both industry and academia to synthesize novel tamoxifen derivatives in order to better understand the mechanism of this drug's action and to generate new agents with reduced side effects for many therapeutic targets. This review article comprises the tamoxifen derivatives reported in the literature in the last few years and we anticipate that it will assist medicinal chemists in the synthesis of novel and pharmacologically potent agents for various therapeutic targets.
|
Displacement of fluorescent estrogen ligand from recombinant human full length untagged ERalpha expressed in Spodoptera frugiperda insect cells at 20 uM measured after 2 hrs by fluorescence polarization assay relative to control
|
Homo sapiens
|
87.4
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of 3-aryl-quinolin derivatives as anti-breast cancer agents targeting ERα and VEGFR-2.
Year : 2019
Volume : 161
First Page : 445
Last Page : 455
Authors : Li X, Wu C, Lin X, Cai X, Liu L, Luo G, You Q, Xiang H.
Abstract : SERMs are a series of important small molecular compounds to modulate estrogen receptor, such as tamoxifen. Although these drugs have showed great benefits in the treatment of breast cancer, the risk of endometrial cancer and endocrine resistance restrict their use. The reasonable designing of multi-target drugs can decrease the side effects and improve the tolerance of antineoplastic agents Studies have identified that VEGFR-2 plays a pivotal role in tumor angiogenesis and drug resistance. Besides, a combination of Tamoxifen and low dose of a VEGFR-2 inhibitor was reported to maximize therapeutic efficacy as well as to retard SERM resistant tumor growth. In this work, a series of 3-aryl-quinolin derivatives were designed to target to ERα and VEGFR-2 to eliminate the disadvantages of SERMs. We identified that compounds 12f and 13f displayed highly ERα binding affinities as well as relative intensity VEGFR-2 inhibitory activities. Moreover, this two compounds exhibited excellent anti-proliferative activities against MCF-7 and HUVEC cell lines with low micromolar IC<sub>50</sub> (1-8 μM). A further study confirmed that compound 13f can reduce the expression of PgR mRNA, arrest cell cycle in MCF-7 breast cancer cells, and restrain the cell migration. Overall, based on the biological activities data, 13f can be chosen as a potential anti-cancer lead compound for further studying.
|
Inhibition of estrogen receptor-alpha (unknown origin) by ELISA
|
Homo sapiens
|
1.5
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based drug design, synthesis, In vitro, and In vivo biological evaluation of indole-based biomimetic analogs targeting estrogen receptor-α inhibition.
Year : 2019
Volume : 166
First Page : 281
Last Page : 290
Authors : Hendy MS, Ali AA, Ahmed L, Hossam R, Mostafa A, Elmazar MM, Naguib BH, Attia YM, Ahmed MS.
Abstract : Offering novel scaffolds targeting estrogen receptor creates huge necessity to overcome the evolving resistance developed by tumors. Structure-based drug design coupled with ring opening strategy of the steroids skeleton revealed the potential of indole-based analogs to be synthesized targeting the ligand binding domain of estrogen receptor-α. In vitro studies revealed the potential of the total sub-classes of the synthesized analogs to show anti-proliferative activity against estrogen receptor-dependent cancer cell lines at IC50 ranging from 28.23 to 57.13 μM. This was further validated by evaluating the potential of the synthesized analogs to compete along with estradiol via ER-α ELISA assay to show inhibitory profile at IC50 ranging from 1.76 to 204.75 nM. Two analogs (YMA-005 and YMA-006) showed significant reduction in tumor size at two dose levels with extensive degeneration and necrosis. Both YMA-005 and YMA-006 showed in-situ reduction of ER-α Immunohistochemical expression at both dose levels. Ultimately, novel analogs of indole-based biomimetic of estrone scaffolds were offered as estrogen receptor-α inhibitors.
|
Inhibition of beta-estradiol-induced estradiol receptor activation (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel compounds that reverse the disease phenotype in Type 2 Gaucher disease patient-derived cells.
Year : 2020
Volume : 30
Issue : 2
First Page : 126806
Last Page : 126806
Authors : Childers W, Fan R, Martinez R, Colussi DJ, Melenski E, Liu Y, Gordon J, Abou-Gharbia M, Jacobson MA.
Abstract : Gaucher disease (GD) results from inherited mutations in the lysosomal enzyme β-glucocerobrosidase (GCase). Currently available treatment options for Type 1 GD are not efficacious for treating neuronopathic Type 2 and 3 GD due to their inability to cross the blood-brain barrier. In an effort to identify small molecules which could be optimized for CNS penetration we identified tamoxifen from a high throughput phenotypic screen on Type 2 GD patient-derived fibroblasts which reversed the disease phenotype. Structure activity studies around this scaffold led to novel molecules that displayed improved potency, efficacy and reduced estrogenic/antiestrogenic activity compared to the original hits. Here we present the design, synthesis and structure activity relationships that led to the lead molecule Compound 31.
|
Displacement of fluorescent estrogen ligand from recombinant human full length untagged ERalpha expressed in baculovirus infected insect cells incubated in dark for 2 hrs by Beacon single-tube fluorescent polarization assay
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg Med Chem
Title : Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening.
Year : 2020
Volume : 28
Issue : 5
First Page : 115261
Last Page : 115261
Authors : Carr M, Knox AJS, Nevin DK, O'Boyle N, Wang S, Egan B, McCabe T, Twamley B, Zisterer DM, Lloyd DG, Meegan MJ.
Abstract : 4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity).
|
Displacement of fluorescent estrogen ligand from recombinant human full length untagged ERbeta expressed in baculovirus infected insect cells incubated in dark for 2 hrs by Beacon single-tube fluorescent polarization assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg Med Chem
Title : Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening.
Year : 2020
Volume : 28
Issue : 5
First Page : 115261
Last Page : 115261
Authors : Carr M, Knox AJS, Nevin DK, O'Boyle N, Wang S, Egan B, McCabe T, Twamley B, Zisterer DM, Lloyd DG, Meegan MJ.
Abstract : 4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity).
|
Antagonist activity at ERalpha (unknown origin)
|
Homo sapiens
|
60.9
nM
|
|
Journal : Bioorg Med Chem
Title : Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening.
Year : 2020
Volume : 28
Issue : 5
First Page : 115261
Last Page : 115261
Authors : Carr M, Knox AJS, Nevin DK, O'Boyle N, Wang S, Egan B, McCabe T, Twamley B, Zisterer DM, Lloyd DG, Meegan MJ.
Abstract : 4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity).
|
Antagonist activity at ERbeta (unknown origin)
|
Homo sapiens
|
188.0
nM
|
|
Journal : Bioorg Med Chem
Title : Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening.
Year : 2020
Volume : 28
Issue : 5
First Page : 115261
Last Page : 115261
Authors : Carr M, Knox AJS, Nevin DK, O'Boyle N, Wang S, Egan B, McCabe T, Twamley B, Zisterer DM, Lloyd DG, Meegan MJ.
Abstract : 4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity).
|
Antiviral activity against pseudotyped Ebola virus - Mayinga, Zaire infected in human A549 cells assessed as reduction in viral infection incubated for 48 hrs by luciferase reporter gene assay
|
Zaire ebolavirus
|
100.0
nM
|
|
Journal : J Med Chem
Title : Screening and Reverse-Engineering of Estrogen Receptor Ligands as Potent Pan-Filovirus Inhibitors.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 11085
Last Page : 11099
Authors : Cooper L,Schafer A,Li Y,Cheng H,Medegan Fagla B,Shen Z,Nowar R,Dye K,Anantpadma M,Davey RA,Thatcher GRJ,Rong L,Xiong R
Abstract : Filoviridae, including Ebola (EBOV) and Marburg (MARV) viruses, are emerging pathogens that pose a serious threat to public health. No agents have been approved to treat filovirus infections, representing a major unmet medical need. The selective estrogen receptor modulator (SERM) toremifene was previously identified from a screen of FDA-approved drugs as a potent EBOV viral entry inhibitor, via binding to EBOV glycoprotein (GP). A focused screen of ER ligands identified ridaifen-B as a potent dual inhibitor of EBOV and MARV. Optimization and reverse-engineering to remove ER activity led to a novel compound 30 (XL-147) showing potent inhibition against infectious EBOV Zaire (0.09 μM) and MARV (0.64 μM). Mutagenesis studies confirmed that inhibition of EBOV viral entry is mediated by the direct interaction with GP. Importantly, compound 30 displayed a broad-spectrum antifilovirus activity against Bundibugyo, Tai Forest, Reston, and Měnglà viruses and is the first submicromolar antiviral agent reported for some of these strains, therefore warranting further development as a pan-filovirus inhibitor.
|
Antiproliferative activity against human MCF-7 cells assessed as inhibition of colony formation measured after 3 weeks by crystal violet staining based soft agar colony formation assay
|
Homo sapiens
|
1.31
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Antiproliferative activity of diarylnaphthylpyrrolidine derivative via dual target inhibition.
Year : 2020
Volume : 188
First Page : 111986
Last Page : 111986
Authors : Verma AK,Fatima K,Dudi RK,Tabassum M,Iqbal H,Kumar Y,Luqman S,Mondhe DM,Chanda D,Khan F,Shanker K,Negi AS
Abstract : Breast cancer is the second leading cause of deaths in women globally. Present communication deals with design and synthesis of a few diarylnaphthyls as possible anti-breast cancer agents. Among the thirty three representatives with significant antiproliferative activity compounds 23 and 50 were quite efficacious against human breast cancer cells. Compound 50 induced apoptosis in both MCF-7 and MDA-MB-231 cells and exerted S phase and G2/M phase arrest respectively via distinct mechanistic pathways. It showed moderate microtubule destabilization. Further, it exhibited DNA topoisomerase-II inhibition effect in MCF-7 cells. It was well tolerable and found safe up to 300 mg/kg dose in Swiss albino mice. The dual action antiproliferative effect of compound 50 is quite interesting and warrants for future development.
|
Cytotoxicity against human MCF7 cells assessed as inhibition of cell growth measured after 72 hrs by MTT assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : RSC Med Chem
Title : Development of potent CPP6-gemcitabine conjugates against human prostate cancer cell line (PC-3)
Year : 2020
Volume : 11
Issue : 2
First Page : 268
Last Page : 273
Authors : Correia, Cristiana, Xavier, Cristina P. R., Duarte, Diana, Ferreira, Abigail, Moreira, Sara, Vasconcelos, M. Helena, Vale, Nuno
Abstract : Gemcitabine (dFdC) is a nucleoside analogue used in the treatment of various cancers, being a standard treatment for advanced pancreatic cancer. The effect of gemcitabine is severely compromised due to its rapid plasma degradation, systemic toxicity and drug resistance, which restricts its therapeutic efficacy. Our main goal was to develop new active conjugates of dFdC with novel cell-penetrating hexapeptides (CPP6) to facilitate intracellular delivery of this drug. All new peptides were prepared by solid phase peptide synthesis (SPPS), purified and characterized by HPLC and LC-MS. Cell-penetrating peptides (CPP) contain a considerably high ratio of positively charged amino acids, imparting them with cationic character. Tumor cells are characterized by an increased anionic nature of their membrane surface, a property that could be used by CPP to target these cells. The BxPC-3, MCF-7 and PC-3 cancer cell lines were used to evaluate the in vitro cytotoxicity of conjugates and the results showed that conjugating dFdC with CPP6 significantly enhanced cell growth inhibitory activity on PC-3 cells, with IC50 between 14 and 15 nM. These new conjugates have potential to become new therapeutic tools for cancer therapy.
|
Antagonist activity at estrogen receptor in human T47D cells incubated for 18 hrs by ultra high sensitivity luminescence reporter gene assay
|
Homo sapiens
|
58.0
nM
|
|
|
Antiproliferative activity against human MCF-7 cells incubated for 72 hrs by Cell-titer Glo assay
|
Homo sapiens
|
200.0
nM
|
|
|
Displacement of fluorescent labeled-ligand from ERalpha (unknown origin) by competitive binding assay
|
Homo sapiens
|
69.0
nM
|
|
