|
Percent of growth inhibition of Cell line CC-1(Cervix) by the compound
|
Homo sapiens
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
Year : 1999
Volume : 42
Issue : 18
First Page : 3602
Last Page : 3614
Authors : Dhar A, Liu S, Klucik J, Berlin KD, Madler MM, Lu S, Ivey RT, Zacheis D, Brown CW, Nelson EC, Birckbichler PJ, Benbrook DM.
Abstract : Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.
|
Percent of growth inhibition of Cell line Caov-3(Ovarian) by the compound
|
Homo sapiens
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
Year : 1999
Volume : 42
Issue : 18
First Page : 3602
Last Page : 3614
Authors : Dhar A, Liu S, Klucik J, Berlin KD, Madler MM, Lu S, Ivey RT, Zacheis D, Brown CW, Nelson EC, Birckbichler PJ, Benbrook DM.
Abstract : Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.
|
Inhibition of chick skin Cytoplasmic retinoic acid binding protein at 100-fold excess ligand
|
Gallus gallus
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Conformationally defined 6-s-trans-retinoic acid analogs. 3. Structure-activity relationships for nuclear receptor binding, transcriptional activity, and cancer chemopreventive activity.
Year : 1996
Volume : 39
Issue : 19
First Page : 3625
Last Page : 3635
Authors : Muccio DD, Brouillette WJ, Alam M, Vaezi MF, Sani BP, Venepally P, Reddy L, Li E, Norris AW, Simpson-Herren L, Hill DL.
Abstract : We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.
|
Inhibition of [3H]ATRA binding to murine Cytoplasmic retinoic acid binding protein (CRABP) type 1
|
Mus musculus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined 6-s-trans-retinoic acid analogs. 3. Structure-activity relationships for nuclear receptor binding, transcriptional activity, and cancer chemopreventive activity.
Year : 1996
Volume : 39
Issue : 19
First Page : 3625
Last Page : 3635
Authors : Muccio DD, Brouillette WJ, Alam M, Vaezi MF, Sani BP, Venepally P, Reddy L, Li E, Norris AW, Simpson-Herren L, Hill DL.
Abstract : We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.
|
Inhibition of [3H]ATRA binding to murine Cytoplasmic retinoic acid binding protein (CRABP) type 2
|
Mus musculus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined 6-s-trans-retinoic acid analogs. 3. Structure-activity relationships for nuclear receptor binding, transcriptional activity, and cancer chemopreventive activity.
Year : 1996
Volume : 39
Issue : 19
First Page : 3625
Last Page : 3635
Authors : Muccio DD, Brouillette WJ, Alam M, Vaezi MF, Sani BP, Venepally P, Reddy L, Li E, Norris AW, Simpson-Herren L, Hill DL.
Abstract : We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.
|
Transglutaminase activity in HL-60 cdm-1 cells
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids.
Year : 1995
Volume : 38
Issue : 15
First Page : 2820
Last Page : 2829
Authors : Beard RL, Chandraratna RA, Colon DF, Gillett SJ, Henry E, Marler DK, Song T, Denys L, Garst ME, Arefieg T.
Abstract : Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.
|
Induction of transglutaminase (TGase) activity in HL-60 cells
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Inhibition of MDA-MB-231 retinoid resistant breast carcinoma cell proliferation at 1 uM
|
Homo sapiens
|
69.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)phenyl]benzoic acid and heterocyclic-bridged analogues are novel retinoic acid receptor subtype and retinoid X receptor alpha agonists.
Year : 2000
Volume : 10
Issue : 12
First Page : 1311
Last Page : 1313
Authors : Dawson MI, Jong L, Hobbs PD, Xiao D, Feng KC, Chao WR, Pan C, Fontana JA, Zhang XK.
Abstract : Aromatic retinoids having a meta-substituted aromatic ring bridge, such as 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)phenyl]benzo ic acid and its 3,5-diaryl-substituted 4,5-dihydroisoxazole analogue, function as retinoid receptor panagonists by activating both retinoic acid and retinoid X receptors to induce gene transcription, and thereby provide novel scaffolds for retinoid drug development. Both classes of these ligand-inducible transcription factors are involved in mediating the inhibitory effects of retinoids on cancer cell growth.
|
Inhibition of MDA-MB-231 cell proliferation after seven days at 12.5 uM
|
Homo sapiens
|
45.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : sp2-bridged diaryl retinoids: effects of bridge-region substitution on retinoid X receptor (RXR) selectivity.
Year : 2000
Volume : 10
Issue : 12
First Page : 1307
Last Page : 1310
Authors : Dawson MI, Hobbs PD, Jong L, Xiao D, Chao WR, Pan C, Zhang XK.
Abstract : RXR class selectivity and RXR transcriptional activation activity compared to those for the retinoic acid receptor subtypes were enhanced on the 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylethenyl)be nzoic acid scaffold and its 3-methyl analogue by replacing their 1,1-ethenyl bridge by a 1,1-(2-methylpropenyl) or cyclopropylidenylmethylene group.
|
Inhibition of Chondrogenesis in day 11 embryonic limb bud cells
|
Mus musculus
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
In vitro inhibition of chondrogenesis in mouse embryo limb bud cells
|
Mus musculus
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids.
Year : 1995
Volume : 38
Issue : 15
First Page : 2820
Last Page : 2829
Authors : Beard RL, Chandraratna RA, Colon DF, Gillett SJ, Henry E, Marler DK, Song T, Denys L, Garst ME, Arefieg T.
Abstract : Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.
|
Transcriptional activation in CV-1 cells expressing retinoic acid receptor RAR alpha
|
None
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Inhibition of [3H]ATRA binding to baculovirus expressed retinoic acid receptor RAR-alpha
|
None
|
90.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Transcriptional activation for RAR alpha receptor
|
None
|
102.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural basis for the differential RXR & RAR activity of stilbene retinoid analogs
Year : 1994
Volume : 4
Issue : 12
First Page : 1447
Last Page : 1452
Authors : Beard RL, Gil DW, Marler DK, Henry E, Colon DF, Gillett SJ, Arefieg T, Breen TS, Krauss H, Davies PJ, Chandraratna RA
|
Transcriptional activation in CV-1 cells expressing retinoic acid receptor RAR beta
|
None
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Inhibition of [3H]ATRA binding to baculovirus expressed retinoic acid receptor RAR-beta
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Transcriptional activation for RAR beta receptor
|
None
|
3.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural basis for the differential RXR & RAR activity of stilbene retinoid analogs
Year : 1994
Volume : 4
Issue : 12
First Page : 1447
Last Page : 1452
Authors : Beard RL, Gil DW, Marler DK, Henry E, Colon DF, Gillett SJ, Arefieg T, Breen TS, Krauss H, Davies PJ, Chandraratna RA
|
Transcriptional activation in CV-1 cells expressing retinoic acid receptor RAR gamma
|
None
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Inhibition of [3H]ATRA binding to baculovirus expressed retinoic acid receptor RAR-gamma
|
None
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Transcriptional activation for RAR gamma receptor
|
None
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural basis for the differential RXR & RAR activity of stilbene retinoid analogs
Year : 1994
Volume : 4
Issue : 12
First Page : 1447
Last Page : 1452
Authors : Beard RL, Gil DW, Marler DK, Henry E, Colon DF, Gillett SJ, Arefieg T, Breen TS, Krauss H, Davies PJ, Chandraratna RA
|
Effective concentration against RAR-alpha receptor
|
None
|
45.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 1. Effect of 9-double bond geometry on retinoid X receptor activity.
Year : 1993
Volume : 36
Issue : 18
First Page : 2605
Last Page : 2613
Authors : Jong L, Lehmann JM, Hobbs PD, Harlev E, Huffman JC, Pfahl M, Dawson MI.
Abstract : A major challenge is the development of retinoids with selective biological activities. Recently, studies on retinoid response mechanisms indicate that retinoids activate two classes of nuclear receptor proteins, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Here, we analyze the activity of a series of (E)- and (Z)-stilbenecarboxylic acids for gene transcriptional activation of the RARs and RXR-alpha to determine the optimum pharmacophore for receptor activation. The data obtained indicate that RAR and RXR response pathways can be separated by using the appropriate ligand. The conformations of (Z)-4-[2-(5-,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prop en-1-yl]benzoic acid (Z)-4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propen-2-yl]benzoic acid were examined by experimental and theoretical methods to establish the appropriate conformation of the latter that specifically activated the retinoid RXR. A palladium(0)-catalyzed aryl bromide-arylboronic acid coupling under nonanhydrous conditions was used to construct a biaryl bond in the conformationally restricted retinoid 2'- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaleny)biphenyl-4-c arboxylic acid, which had RXR activity.
|
Effective concentration against RAR-gamma receptor
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 1. Effect of 9-double bond geometry on retinoid X receptor activity.
Year : 1993
Volume : 36
Issue : 18
First Page : 2605
Last Page : 2613
Authors : Jong L, Lehmann JM, Hobbs PD, Harlev E, Huffman JC, Pfahl M, Dawson MI.
Abstract : A major challenge is the development of retinoids with selective biological activities. Recently, studies on retinoid response mechanisms indicate that retinoids activate two classes of nuclear receptor proteins, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Here, we analyze the activity of a series of (E)- and (Z)-stilbenecarboxylic acids for gene transcriptional activation of the RARs and RXR-alpha to determine the optimum pharmacophore for receptor activation. The data obtained indicate that RAR and RXR response pathways can be separated by using the appropriate ligand. The conformations of (Z)-4-[2-(5-,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prop en-1-yl]benzoic acid (Z)-4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propen-2-yl]benzoic acid were examined by experimental and theoretical methods to establish the appropriate conformation of the latter that specifically activated the retinoid RXR. A palladium(0)-catalyzed aryl bromide-arylboronic acid coupling under nonanhydrous conditions was used to construct a biaryl bond in the conformationally restricted retinoid 2'- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaleny)biphenyl-4-c arboxylic acid, which had RXR activity.
|
Transcriptional activation in CV-1 cells expressing retinoid X receptor RXR alpha
|
None
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Inhibition of [3H]9-cis-retinoic acid binding to baculovirus expressed retinoic acid receptor RXR-alpha
|
None
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Dissociation constant for binding to Retinoic acid receptor RXR-alpha
|
Homo sapiens
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and characterization of a new RXR agonist based on the 6-tert-butyl-1,1-dimethylindanyl structure.
Year : 2002
Volume : 12
Issue : 18
First Page : 2607
Last Page : 2609
Authors : Domínguez B, Vega MJ, Sussman F, de Lera AR.
Abstract : A new ligand for RXR is described, which is based on a 6-tert-butyl-1,1-dimethylindanyl skeleton as bioisostere of the hydrophobic retinoid region. The Stille cross-coupling reaction allowed the attachment of the polyene side chain to the indanyl ring. Docking studies were carried out to explain the RXR binding profile of this analogue.
|
Transcriptional activation for RXR alpha receptor
|
None
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural basis for the differential RXR & RAR activity of stilbene retinoid analogs
Year : 1994
Volume : 4
Issue : 12
First Page : 1447
Last Page : 1452
Authors : Beard RL, Gil DW, Marler DK, Henry E, Colon DF, Gillett SJ, Arefieg T, Breen TS, Krauss H, Davies PJ, Chandraratna RA
|
Transcriptional activation in CV-1 cells expressing retinoid X receptor RXR beta
|
None
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Inhibition of [3H]9-cis-retinoic acid binding to baculovirus expressed retinoic acid receptor RXR-beta
|
None
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Transcriptional activation in CV-1 cells expressing retinoid X receptor RXR gamma
|
None
|
4.5
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Inhibition of [3H]9-cis-retinoic acid binding to baculovirus expressed retinoic acid receptor RXR-gamma
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes.
Year : 2001
Volume : 44
Issue : 14
First Page : 2298
Last Page : 2303
Authors : Vuligonda V, Thacher SM, Chandraratna RA.
Abstract : The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
|
Effective concentration against RXR-alpha receptor
|
None
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 1. Effect of 9-double bond geometry on retinoid X receptor activity.
Year : 1993
Volume : 36
Issue : 18
First Page : 2605
Last Page : 2613
Authors : Jong L, Lehmann JM, Hobbs PD, Harlev E, Huffman JC, Pfahl M, Dawson MI.
Abstract : A major challenge is the development of retinoids with selective biological activities. Recently, studies on retinoid response mechanisms indicate that retinoids activate two classes of nuclear receptor proteins, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Here, we analyze the activity of a series of (E)- and (Z)-stilbenecarboxylic acids for gene transcriptional activation of the RARs and RXR-alpha to determine the optimum pharmacophore for receptor activation. The data obtained indicate that RAR and RXR response pathways can be separated by using the appropriate ligand. The conformations of (Z)-4-[2-(5-,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prop en-1-yl]benzoic acid (Z)-4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propen-2-yl]benzoic acid were examined by experimental and theoretical methods to establish the appropriate conformation of the latter that specifically activated the retinoid RXR. A palladium(0)-catalyzed aryl bromide-arylboronic acid coupling under nonanhydrous conditions was used to construct a biaryl bond in the conformationally restricted retinoid 2'- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaleny)biphenyl-4-c arboxylic acid, which had RXR activity.
|
Transcriptional activation of Retinoic acid receptor RAR alpha
|
Cercopithecidae
|
191.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Inhibition of [3H]ATRA binding to mouse Retinoic acid receptor RAR alpha
|
Mus musculus
|
31.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined 6-s-trans-retinoic acid analogs. 3. Structure-activity relationships for nuclear receptor binding, transcriptional activity, and cancer chemopreventive activity.
Year : 1996
Volume : 39
Issue : 19
First Page : 3625
Last Page : 3635
Authors : Muccio DD, Brouillette WJ, Alam M, Vaezi MF, Sani BP, Venepally P, Reddy L, Li E, Norris AW, Simpson-Herren L, Hill DL.
Abstract : We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.
|
Dissociation constant for binding to Retinoic acid receptor alpha
|
Homo sapiens
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Percent inhibition of [3H]ATRA binding to mouse Retinoic acid receptor RAR alpha
|
Mus musculus
|
95.0
%
|
|
Journal : J. Med. Chem.
Title : Conformationally defined 6-s-trans-retinoic acid analogs. 3. Structure-activity relationships for nuclear receptor binding, transcriptional activity, and cancer chemopreventive activity.
Year : 1996
Volume : 39
Issue : 19
First Page : 3625
Last Page : 3635
Authors : Muccio DD, Brouillette WJ, Alam M, Vaezi MF, Sani BP, Venepally P, Reddy L, Li E, Norris AW, Simpson-Herren L, Hill DL.
Abstract : We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.
|
Binding affinity against retinoic Acid alpha receptors co-transfected into CV-1 cells
|
None
|
191.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Transcriptional activation in CV-1 cells expressing Retinoic acid receptor RAR alpha
|
None
|
304.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Compound was tested for functional activity in CV-1 cells transfected with an expression vector for retinoic acid receptor alpha using transactivation assay
|
None
|
191.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Relative activity against Retinoic acid receptor RAR alpha compared to ATRA
|
None
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.
Year : 1995
Volume : 38
Issue : 17
First Page : 3368
Last Page : 3383
Authors : Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao WR, Pfahl M, Lee MO, Shroot B, Pfahl M.
Abstract : The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessary to confer RXR selectivity were established by evaluating the ability of 21 conformationally restricted retinoids to activate the TREpal retinoic acid receptor response element for gene transcription in the presence of one of the three RAR subtypes or RXR alpha. In contrast to those retinoids selective for the RARs, these RXR-selective retinoids have one less atom in the bridge linking the hydrophobic and carboxylic acid termini of the retinoid skeleton. Therefore, a one-carbon bridge replaces the 19-methyl group and 9E-double bond of 9-cis-retinoic acid and is further functionalized by inclusion in an isopropylidene group, a dioxolane ring, or a cyclopropane ring for optimal RXR alpha activity and selectivity. In addition, the beta-geranylidene and 20-methyl-(11E,13E)-dienoic acid groups of 9-cis-retinoic acid are replaced by a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl ring and a 4-carboxylphenyl ring, respectively, for optimal activation and selectivity. RXR alpha selectivity is reduced on replacement of the 4-carboxylphenyl group by a 2-carboxyl-5-thienyl group or the 9-cis-retinoic acid methylpentadienoic acid terminus.
|
Binding affinity against retinoic Acid alpha receptor using [3H]- -9-cis-Retinoic Acid in competitive binding assay
|
None
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Inhibition of [3H]RA binding to retinoic acid receptor RAR alpha
|
None
|
93.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Stereoselective synthesis and receptor activity of conformationally defined retinoid X receptor selective ligands.
Year : 1999
Volume : 9
Issue : 4
First Page : 589
Last Page : 594
Authors : Vuligonda V, Garst ME, Chandraratna RA.
Abstract : Retinoid X Receptor (RXR) specific ligands are currently being investigated for the treatment of metabolic diseases such as type II diabetes. We report the synthesis of conformationally locked retinoids, which are potent RXR selective ligands, and the attempted synthesis of 9-cyclopropyl locked analogs of RA and 9-cis RA.
|
Compound was tested for binding affinity against retinoic acid receptor using 5 nM of [3H]RA as a radioligand in baculovirus expressed receptor
|
None
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Inhibition of [3H]ATRA binding to Retinoic acid receptor RAR alpha
|
None
|
22.3
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Agonist activity for retinoic acid receptor RAR beta in transcriptional activation assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Differential RXR & RAR activity of stilbene retinoid analogs bearing thiazole and imidazole carboxylic acids
Year : 1995
Volume : 5
Issue : 22
First Page : 2729
Last Page : 2734
Authors : Beard RL, Colon DF, Klein ES, Vorse KA, Chandraratna RA
|
Transcriptional activation of Retinoic acid receptor RAR beta
|
Homo sapiens
|
3.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids.
Year : 1995
Volume : 38
Issue : 15
First Page : 2820
Last Page : 2829
Authors : Beard RL, Chandraratna RA, Colon DF, Gillett SJ, Henry E, Marler DK, Song T, Denys L, Garst ME, Arefieg T.
Abstract : Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.
|
Transcriptional activation in CV-1 cells expressing human Retinoic acid receptor RAR beta
|
Homo sapiens
|
29.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Inhibition of [3H]-ATRA binding to human Retinoic acid receptor RAR beta
|
Homo sapiens
|
97.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Transcriptional activation of Retinoic acid receptor RAR beta
|
Cercopithecidae
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Dissociation constant for binding to Retinoic acid receptor beta
|
Mus musculus
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Transcriptional activation in CV-1 cells expressing Retinoic acid receptor RAR beta
|
None
|
52.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Compound was tested for functional activity in CV-1 cells transfected with an expression vector for retinoic acid receptor beta using transactivation assay
|
None
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Effective concentration against Retinoic acid receptor beta
|
None
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 1. Effect of 9-double bond geometry on retinoid X receptor activity.
Year : 1993
Volume : 36
Issue : 18
First Page : 2605
Last Page : 2613
Authors : Jong L, Lehmann JM, Hobbs PD, Harlev E, Huffman JC, Pfahl M, Dawson MI.
Abstract : A major challenge is the development of retinoids with selective biological activities. Recently, studies on retinoid response mechanisms indicate that retinoids activate two classes of nuclear receptor proteins, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Here, we analyze the activity of a series of (E)- and (Z)-stilbenecarboxylic acids for gene transcriptional activation of the RARs and RXR-alpha to determine the optimum pharmacophore for receptor activation. The data obtained indicate that RAR and RXR response pathways can be separated by using the appropriate ligand. The conformations of (Z)-4-[2-(5-,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prop en-1-yl]benzoic acid (Z)-4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propen-2-yl]benzoic acid were examined by experimental and theoretical methods to establish the appropriate conformation of the latter that specifically activated the retinoid RXR. A palladium(0)-catalyzed aryl bromide-arylboronic acid coupling under nonanhydrous conditions was used to construct a biaryl bond in the conformationally restricted retinoid 2'- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaleny)biphenyl-4-c arboxylic acid, which had RXR activity.
|
Inhibition of [3H]RA binding to retinoic acid receptor RAR beta
|
None
|
97.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Stereoselective synthesis and receptor activity of conformationally defined retinoid X receptor selective ligands.
Year : 1999
Volume : 9
Issue : 4
First Page : 589
Last Page : 594
Authors : Vuligonda V, Garst ME, Chandraratna RA.
Abstract : Retinoid X Receptor (RXR) specific ligands are currently being investigated for the treatment of metabolic diseases such as type II diabetes. We report the synthesis of conformationally locked retinoids, which are potent RXR selective ligands, and the attempted synthesis of 9-cyclopropyl locked analogs of RA and 9-cis RA.
|
Compound was tested for binding affinity against retinoic acid receptor using 5 nM of [3H]RA as a radioligand in baculovirus expressed receptor
|
None
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Inhibition of [3H]ATRA binding to Retinoic acid receptor RAR beta
|
None
|
10.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Agonist activity for retinoic acid receptor RAR gamma in transcriptional activation assay
|
Homo sapiens
|
45.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Differential RXR & RAR activity of stilbene retinoid analogs bearing thiazole and imidazole carboxylic acids
Year : 1995
Volume : 5
Issue : 22
First Page : 2729
Last Page : 2734
Authors : Beard RL, Colon DF, Klein ES, Vorse KA, Chandraratna RA
|
Transcriptional activation of Retinoic acid receptor RAR gamma
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids.
Year : 1995
Volume : 38
Issue : 15
First Page : 2820
Last Page : 2829
Authors : Beard RL, Chandraratna RA, Colon DF, Gillett SJ, Henry E, Marler DK, Song T, Denys L, Garst ME, Arefieg T.
Abstract : Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.
|
Transcriptional activation in CV-1 cells expressing human Retinoic acid receptor RAR gamma
|
Homo sapiens
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Inhibition of [3H]ATRA binding to human Retinoic acid receptor RAR gamma
|
Homo sapiens
|
148.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Agonistic activity towards retinoic acid receptor-gamma
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H-10,11,12,13-tetrahydro-10, 10,13,13,15-pentamethyldinaphtho[2,3-b][1,2-e]diazepin-7-yl) benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e] [1,4]diazepin-11-yl]-benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR-antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.
|
Transcriptional activation of Retinoic acid receptor RAR gamma
|
Cercopithecidae
|
45.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Dissociation constant for binding to Retinoic acid receptor gamma
|
Mus musculus
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Transcriptional activation in CV-1 cells expressing Retinoic acid receptor RAR gamma
|
None
|
74.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Compound was tested for functional activity in CV-1 cells transfected with an expression vector for retinoic acid receptor gamma using transactivation assay
|
None
|
45.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Inhibition of [3H]RA binding to retinoic acid receptor RAR gamma
|
None
|
148.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Stereoselective synthesis and receptor activity of conformationally defined retinoid X receptor selective ligands.
Year : 1999
Volume : 9
Issue : 4
First Page : 589
Last Page : 594
Authors : Vuligonda V, Garst ME, Chandraratna RA.
Abstract : Retinoid X Receptor (RXR) specific ligands are currently being investigated for the treatment of metabolic diseases such as type II diabetes. We report the synthesis of conformationally locked retinoids, which are potent RXR selective ligands, and the attempted synthesis of 9-cyclopropyl locked analogs of RA and 9-cis RA.
|
Compound was tested for binding affinity against retinoic acid receptor using 5 nM of [3H]RA as a radioligand in baculovirus expressed receptor
|
None
|
22.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Inhibition of [3H]ATRA binding to Retinoic acid receptor RAR gamma
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Agonistic activity towards retinoid X receptor-alpha
|
Homo sapiens
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H-10,11,12,13-tetrahydro-10, 10,13,13,15-pentamethyldinaphtho[2,3-b][1,2-e]diazepin-7-yl) benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e] [1,4]diazepin-11-yl]-benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR-antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.
|
Binding affinity against retinoic Acid X alpha receptors co-transfected into CV-1 cells
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Compound was tested for functional activity in CV-1 cells transfected with an expression vector for retinoid X receptor alpha using transactivation assay
|
None
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Binding affinity against retinoic Acid X alpha receptor using [3H]- -9-cis-Retinoic Acid in competitive binding assay
|
None
|
32.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Compound was tested for binding affinity against retinoid X receptor using 5 nM of [3H]-9-cis-RA as a radioligand in baculovirus expressed receptor
|
None
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Agonistic activity towards retinoid X receptor-beta
|
Homo sapiens
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H-10,11,12,13-tetrahydro-10, 10,13,13,15-pentamethyldinaphtho[2,3-b][1,2-e]diazepin-7-yl) benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e] [1,4]diazepin-11-yl]-benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR-antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.
|
Inhibition of binding to human Retinoic acid receptor RXR DEF domain
|
Homo sapiens
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined 6-s-trans-retinoic acid analogs. 3. Structure-activity relationships for nuclear receptor binding, transcriptional activity, and cancer chemopreventive activity.
Year : 1996
Volume : 39
Issue : 19
First Page : 3625
Last Page : 3635
Authors : Muccio DD, Brouillette WJ, Alam M, Vaezi MF, Sani BP, Venepally P, Reddy L, Li E, Norris AW, Simpson-Herren L, Hill DL.
Abstract : We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.
|
Agonist activity for retinoic acid receptor RXR alpha in transcriptional activation assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Differential RXR & RAR activity of stilbene retinoid analogs bearing thiazole and imidazole carboxylic acids
Year : 1995
Volume : 5
Issue : 22
First Page : 2729
Last Page : 2734
Authors : Beard RL, Colon DF, Klein ES, Vorse KA, Chandraratna RA
|
Binding affinity against retinoic Acid X beta receptors co-transfected into CV-1 cells
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Compound was tested for functional activity in CV-1 cells transfected with an expression vector for retinoid X receptor beta using transactivation assay
|
None
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Binding affinity against retinoic Acid X beta receptor using [3H]- -9-cis-Retinoic Acid in competitive binding assay
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Compound was tested for binding affinity against retinoid X receptor using 5 nM of [3H]9-cis-RA as a radioligand in baculovirus expressed receptor
|
None
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Agonistic activity towards retinoid X receptor-gamma
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H-10,11,12,13-tetrahydro-10, 10,13,13,15-pentamethyldinaphtho[2,3-b][1,2-e]diazepin-7-yl) benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e] [1,4]diazepin-11-yl]-benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR-antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.
|
Binding affinity against retinoic Acid X gamma receptors co-transfected into CV-1 cells
|
None
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Compound was tested for functional activity in CV-1 cells transfected with an expression vector for retinoid X receptor gamma using transactivation assay
|
None
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Binding affinity against retinoic Acid X gamma receptor using [3H]- -9-cis-Retinoic Acid in competitive binding assay
|
None
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Compound was tested for binding affinity against retinoid X receptor using 5 nM of [3H]9-cis-RA as a radioligand in baculovirus expressed receptor
|
None
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of highly potent RXR-specific retinoids: The use of a cyclopropyl group as a double bond isostere
Year : 1996
Volume : 6
Issue : 2
First Page : 213
Last Page : 218
Authors : Vuligonda V, Lin Y, Chandraratna RA
|
Transcriptional activation of Retinoic acid receptor RAR alpha
|
None
|
102.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies of novel heteroretinoids: induction of apoptosis in the HL-60 cell line by a novel isoxazole-containing heteroretinoid.
Year : 1999
Volume : 42
Issue : 24
First Page : 4961
Last Page : 4969
Authors : Simoni D, Invidiata FP, Rondanin R, Grimaudo S, Cannizzo G, Barbusca E, Porretto F, D'Alessandro N, Tolomeo M.
Abstract : In a search for retinoic acid receptor (RAR and RXR)-selective ligands, a series of isoxazole retinoids was synthesized and evaluated in vitro in transcriptional activation and competition binding assays for RARs and RXRs. In addition, these compounds were evaluated for their differentiating, cytotoxic, and apoptotic activities. In general, these derivatives showed scarcely any binding affinity and were not active in the transcriptional assay. However, among these isoxazole derivatives, the cis-isomer 14b was identified as a potent inducer of apoptosis, and its activity was found to be 6.5 and 4 times superior than that of 13-cis- and 9-cis-retinoic acids, respectively. On the other hand, compound 13b, which has the trans stereochemistry at the double bond, was found not to be active in the apoptotic assay, but it was endowed with appreciable differentiating activity. Therefore, it seems that the different stereochemistry of the double bond may be associated with a different biological activity: potent apoptotic activity for the cis-isomer but differentiating activity for the trans structure. This biological behavior was found, at least in part, for the 9-cis- and 13-cis-retinoic acids with respect to the all-trans-retinoic acid. Thus, structure 14b could offer an interesting model for the design of new compounds endowed with apoptotic activity.
|
Binding affinity against retinoic Acid beta receptors co-transfected into CV-1 cells
|
None
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Binding affinity against retinoic Acid beta receptor using [3H]- -9-cis-Retinoic Acid in competitive binding assay
|
None
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Transcriptional activation of Retinoic acid receptor RAR beta
|
None
|
3.3
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies of novel heteroretinoids: induction of apoptosis in the HL-60 cell line by a novel isoxazole-containing heteroretinoid.
Year : 1999
Volume : 42
Issue : 24
First Page : 4961
Last Page : 4969
Authors : Simoni D, Invidiata FP, Rondanin R, Grimaudo S, Cannizzo G, Barbusca E, Porretto F, D'Alessandro N, Tolomeo M.
Abstract : In a search for retinoic acid receptor (RAR and RXR)-selective ligands, a series of isoxazole retinoids was synthesized and evaluated in vitro in transcriptional activation and competition binding assays for RARs and RXRs. In addition, these compounds were evaluated for their differentiating, cytotoxic, and apoptotic activities. In general, these derivatives showed scarcely any binding affinity and were not active in the transcriptional assay. However, among these isoxazole derivatives, the cis-isomer 14b was identified as a potent inducer of apoptosis, and its activity was found to be 6.5 and 4 times superior than that of 13-cis- and 9-cis-retinoic acids, respectively. On the other hand, compound 13b, which has the trans stereochemistry at the double bond, was found not to be active in the apoptotic assay, but it was endowed with appreciable differentiating activity. Therefore, it seems that the different stereochemistry of the double bond may be associated with a different biological activity: potent apoptotic activity for the cis-isomer but differentiating activity for the trans structure. This biological behavior was found, at least in part, for the 9-cis- and 13-cis-retinoic acids with respect to the all-trans-retinoic acid. Thus, structure 14b could offer an interesting model for the design of new compounds endowed with apoptotic activity.
|
Binding affinity against retinoic Acid gamma receptors co-transfected into CV-1 cells
|
None
|
45.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Binding affinity against retinoic Acid gamma receptor using [3H]- -9-cis-Retinoic Acid in competitive binding assay
|
None
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.
Year : 1994
Volume : 37
Issue : 3
First Page : 408
Last Page : 414
Authors : Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA.
Abstract : all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
|
Transcriptional activation of Retinoic acid receptor RAR gamma
|
None
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies of novel heteroretinoids: induction of apoptosis in the HL-60 cell line by a novel isoxazole-containing heteroretinoid.
Year : 1999
Volume : 42
Issue : 24
First Page : 4961
Last Page : 4969
Authors : Simoni D, Invidiata FP, Rondanin R, Grimaudo S, Cannizzo G, Barbusca E, Porretto F, D'Alessandro N, Tolomeo M.
Abstract : In a search for retinoic acid receptor (RAR and RXR)-selective ligands, a series of isoxazole retinoids was synthesized and evaluated in vitro in transcriptional activation and competition binding assays for RARs and RXRs. In addition, these compounds were evaluated for their differentiating, cytotoxic, and apoptotic activities. In general, these derivatives showed scarcely any binding affinity and were not active in the transcriptional assay. However, among these isoxazole derivatives, the cis-isomer 14b was identified as a potent inducer of apoptosis, and its activity was found to be 6.5 and 4 times superior than that of 13-cis- and 9-cis-retinoic acids, respectively. On the other hand, compound 13b, which has the trans stereochemistry at the double bond, was found not to be active in the apoptotic assay, but it was endowed with appreciable differentiating activity. Therefore, it seems that the different stereochemistry of the double bond may be associated with a different biological activity: potent apoptotic activity for the cis-isomer but differentiating activity for the trans structure. This biological behavior was found, at least in part, for the 9-cis- and 13-cis-retinoic acids with respect to the all-trans-retinoic acid. Thus, structure 14b could offer an interesting model for the design of new compounds endowed with apoptotic activity.
|
Transcriptional activation of Retinoid X receptor RXR alpha
|
Homo sapiens
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids.
Year : 1995
Volume : 38
Issue : 15
First Page : 2820
Last Page : 2829
Authors : Beard RL, Chandraratna RA, Colon DF, Gillett SJ, Henry E, Marler DK, Song T, Denys L, Garst ME, Arefieg T.
Abstract : Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.
|
Transcriptional activation in CV-1 cells expressing human Retinoid X receptor RXR-alpha
|
Homo sapiens
|
195.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Inhibition of [3H]9-cis-RA binding to human Retinoid X receptor RXR alpha
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Inhibition of [3H]targretin binding to Retinoid X receptor RXR alpha
|
Homo sapiens
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of the first retinoid X, receptor homodimer antagonist.
Year : 1996
Volume : 39
Issue : 17
First Page : 3229
Last Page : 3234
Authors : Canan Koch SS, Dardashti LJ, Hebert JJ, White SK, Croston GE, Flatten KS, Heyman RA, Nadzan AM.
|
Transcriptional activation of Retinoid X receptor RXR alpha
|
Cercopithecidae
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Inhibition of [3H]-ATRA binding to mouse Retinoic acid receptor RXR alpha
|
Mus musculus
|
82.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined 6-s-trans-retinoic acid analogs. 3. Structure-activity relationships for nuclear receptor binding, transcriptional activity, and cancer chemopreventive activity.
Year : 1996
Volume : 39
Issue : 19
First Page : 3625
Last Page : 3635
Authors : Muccio DD, Brouillette WJ, Alam M, Vaezi MF, Sani BP, Venepally P, Reddy L, Li E, Norris AW, Simpson-Herren L, Hill DL.
Abstract : We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.
|
Dissociation constant for binding to Retinoid X receptor alpha
|
Mus musculus
|
32.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Percent inhibition of [3H]ATRA binding to mouse Retinoic acid receptor RXR alpha
|
Mus musculus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Conformationally defined 6-s-trans-retinoic acid analogs. 3. Structure-activity relationships for nuclear receptor binding, transcriptional activity, and cancer chemopreventive activity.
Year : 1996
Volume : 39
Issue : 19
First Page : 3625
Last Page : 3635
Authors : Muccio DD, Brouillette WJ, Alam M, Vaezi MF, Sani BP, Venepally P, Reddy L, Li E, Norris AW, Simpson-Herren L, Hill DL.
Abstract : We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.
|
Transcriptional activation in CV-1 cells expressing Retinoid X receptor RXR alpha
|
None
|
316.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Effective concentration against Retinoic acid receptor RXR-alpha
|
None
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.
Year : 1995
Volume : 38
Issue : 17
First Page : 3368
Last Page : 3383
Authors : Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao WR, Pfahl M, Lee MO, Shroot B, Pfahl M.
Abstract : The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessary to confer RXR selectivity were established by evaluating the ability of 21 conformationally restricted retinoids to activate the TREpal retinoic acid receptor response element for gene transcription in the presence of one of the three RAR subtypes or RXR alpha. In contrast to those retinoids selective for the RARs, these RXR-selective retinoids have one less atom in the bridge linking the hydrophobic and carboxylic acid termini of the retinoid skeleton. Therefore, a one-carbon bridge replaces the 19-methyl group and 9E-double bond of 9-cis-retinoic acid and is further functionalized by inclusion in an isopropylidene group, a dioxolane ring, or a cyclopropane ring for optimal RXR alpha activity and selectivity. In addition, the beta-geranylidene and 20-methyl-(11E,13E)-dienoic acid groups of 9-cis-retinoic acid are replaced by a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl ring and a 4-carboxylphenyl ring, respectively, for optimal activation and selectivity. RXR alpha selectivity is reduced on replacement of the 4-carboxylphenyl group by a 2-carboxyl-5-thienyl group or the 9-cis-retinoic acid methylpentadienoic acid terminus.
|
Inhibition of [3H]-9-cis RA binding to Retinoid X receptor RXR gamma
|
None
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Stereoselective synthesis and receptor activity of conformationally defined retinoid X receptor selective ligands.
Year : 1999
Volume : 9
Issue : 4
First Page : 589
Last Page : 594
Authors : Vuligonda V, Garst ME, Chandraratna RA.
Abstract : Retinoid X Receptor (RXR) specific ligands are currently being investigated for the treatment of metabolic diseases such as type II diabetes. We report the synthesis of conformationally locked retinoids, which are potent RXR selective ligands, and the attempted synthesis of 9-cyclopropyl locked analogs of RA and 9-cis RA.
|
Inhibition of [3H]9-cis-RA binding to Retinoid X receptor RXR alpha
|
None
|
8.4
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Transcriptional activation of Retinoid X receptor RXR alpha
|
None
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies of novel heteroretinoids: induction of apoptosis in the HL-60 cell line by a novel isoxazole-containing heteroretinoid.
Year : 1999
Volume : 42
Issue : 24
First Page : 4961
Last Page : 4969
Authors : Simoni D, Invidiata FP, Rondanin R, Grimaudo S, Cannizzo G, Barbusca E, Porretto F, D'Alessandro N, Tolomeo M.
Abstract : In a search for retinoic acid receptor (RAR and RXR)-selective ligands, a series of isoxazole retinoids was synthesized and evaluated in vitro in transcriptional activation and competition binding assays for RARs and RXRs. In addition, these compounds were evaluated for their differentiating, cytotoxic, and apoptotic activities. In general, these derivatives showed scarcely any binding affinity and were not active in the transcriptional assay. However, among these isoxazole derivatives, the cis-isomer 14b was identified as a potent inducer of apoptosis, and its activity was found to be 6.5 and 4 times superior than that of 13-cis- and 9-cis-retinoic acids, respectively. On the other hand, compound 13b, which has the trans stereochemistry at the double bond, was found not to be active in the apoptotic assay, but it was endowed with appreciable differentiating activity. Therefore, it seems that the different stereochemistry of the double bond may be associated with a different biological activity: potent apoptotic activity for the cis-isomer but differentiating activity for the trans structure. This biological behavior was found, at least in part, for the 9-cis- and 13-cis-retinoic acids with respect to the all-trans-retinoic acid. Thus, structure 14b could offer an interesting model for the design of new compounds endowed with apoptotic activity.
|
Agonist activity for retinoic acid receptor RXR beta in transcriptional activation assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Differential RXR & RAR activity of stilbene retinoid analogs bearing thiazole and imidazole carboxylic acids
Year : 1995
Volume : 5
Issue : 22
First Page : 2729
Last Page : 2734
Authors : Beard RL, Colon DF, Klein ES, Vorse KA, Chandraratna RA
|
Inhibition of [3H]-Targretin binding to Retinoid X receptor RXR beta
|
Homo sapiens
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of the first retinoid X, receptor homodimer antagonist.
Year : 1996
Volume : 39
Issue : 17
First Page : 3229
Last Page : 3234
Authors : Canan Koch SS, Dardashti LJ, Hebert JJ, White SK, Croston GE, Flatten KS, Heyman RA, Nadzan AM.
|
Transcriptional activation of Retinoid X receptor RXR beta
|
Cercopithecidae
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Transcriptional activation in CV-1 cells expressing mouse Retinoid X receptor RXR beta
|
Mus musculus
|
128.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Dissociation constant for binding to Retinoid X receptor beta
|
Mus musculus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Inhibition of [3H]9-cis-RA binding to mouse Retinoid X receptor RXR beta
|
Mus musculus
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Transcriptional activation in CV-1 cells expressing Retinoid X receptor RXR beta
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Effective concentrations against Retinoic acid receptor RXR-beta
|
None
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.
Year : 1995
Volume : 38
Issue : 17
First Page : 3368
Last Page : 3383
Authors : Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao WR, Pfahl M, Lee MO, Shroot B, Pfahl M.
Abstract : The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessary to confer RXR selectivity were established by evaluating the ability of 21 conformationally restricted retinoids to activate the TREpal retinoic acid receptor response element for gene transcription in the presence of one of the three RAR subtypes or RXR alpha. In contrast to those retinoids selective for the RARs, these RXR-selective retinoids have one less atom in the bridge linking the hydrophobic and carboxylic acid termini of the retinoid skeleton. Therefore, a one-carbon bridge replaces the 19-methyl group and 9E-double bond of 9-cis-retinoic acid and is further functionalized by inclusion in an isopropylidene group, a dioxolane ring, or a cyclopropane ring for optimal RXR alpha activity and selectivity. In addition, the beta-geranylidene and 20-methyl-(11E,13E)-dienoic acid groups of 9-cis-retinoic acid are replaced by a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl ring and a 4-carboxylphenyl ring, respectively, for optimal activation and selectivity. RXR alpha selectivity is reduced on replacement of the 4-carboxylphenyl group by a 2-carboxyl-5-thienyl group or the 9-cis-retinoic acid methylpentadienoic acid terminus.
|
Inhibition of [3H]-9-cis RA binding to Retinoid X receptor RXR beta
|
None
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Stereoselective synthesis and receptor activity of conformationally defined retinoid X receptor selective ligands.
Year : 1999
Volume : 9
Issue : 4
First Page : 589
Last Page : 594
Authors : Vuligonda V, Garst ME, Chandraratna RA.
Abstract : Retinoid X Receptor (RXR) specific ligands are currently being investigated for the treatment of metabolic diseases such as type II diabetes. We report the synthesis of conformationally locked retinoids, which are potent RXR selective ligands, and the attempted synthesis of 9-cyclopropyl locked analogs of RA and 9-cis RA.
|
Inhibition of [3H]9-cis-RA binding to Retinoid X receptor RXR beta
|
None
|
7.4
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Agonist activity for retinoic acid receptor RXR gamma in transcriptional activation assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Differential RXR & RAR activity of stilbene retinoid analogs bearing thiazole and imidazole carboxylic acids
Year : 1995
Volume : 5
Issue : 22
First Page : 2729
Last Page : 2734
Authors : Beard RL, Colon DF, Klein ES, Vorse KA, Chandraratna RA
|
Inhibition of [3H]targretin binding to Retinoid X receptor RXR gamma
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of the first retinoid X, receptor homodimer antagonist.
Year : 1996
Volume : 39
Issue : 17
First Page : 3229
Last Page : 3234
Authors : Canan Koch SS, Dardashti LJ, Hebert JJ, White SK, Croston GE, Flatten KS, Heyman RA, Nadzan AM.
|
Transcriptional activation of Retinoid X receptor RXR gamma
|
Cercopithecidae
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Transcriptional activation in CV-1 cells expressing mouse Retinoid X receptor RXR gamma
|
Mus musculus
|
124.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Dissociation constant for binding to Retinoid X receptor gamma
|
Mus musculus
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
Year : 1996
Volume : 39
Issue : 18
First Page : 3556
Last Page : 3563
Authors : Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA.
Abstract : Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
|
Inhibition of [3H]-9-cis-RA binding to human Retinoid X receptor RXR gamma
|
Homo sapiens
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Transcriptional activation in CV-1 cells expressing Retinoid X receptor RXR gamma
|
None
|
219.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Effective concentrations against Retinoic acid receptor RXR-gamma
|
None
|
4.3
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.
Year : 1995
Volume : 38
Issue : 17
First Page : 3368
Last Page : 3383
Authors : Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao WR, Pfahl M, Lee MO, Shroot B, Pfahl M.
Abstract : The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessary to confer RXR selectivity were established by evaluating the ability of 21 conformationally restricted retinoids to activate the TREpal retinoic acid receptor response element for gene transcription in the presence of one of the three RAR subtypes or RXR alpha. In contrast to those retinoids selective for the RARs, these RXR-selective retinoids have one less atom in the bridge linking the hydrophobic and carboxylic acid termini of the retinoid skeleton. Therefore, a one-carbon bridge replaces the 19-methyl group and 9E-double bond of 9-cis-retinoic acid and is further functionalized by inclusion in an isopropylidene group, a dioxolane ring, or a cyclopropane ring for optimal RXR alpha activity and selectivity. In addition, the beta-geranylidene and 20-methyl-(11E,13E)-dienoic acid groups of 9-cis-retinoic acid are replaced by a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl ring and a 4-carboxylphenyl ring, respectively, for optimal activation and selectivity. RXR alpha selectivity is reduced on replacement of the 4-carboxylphenyl group by a 2-carboxyl-5-thienyl group or the 9-cis-retinoic acid methylpentadienoic acid terminus.
|
Inhibition of [3H]-9-cis RA binding to Retinoid X receptor RXR gamma
|
None
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Stereoselective synthesis and receptor activity of conformationally defined retinoid X receptor selective ligands.
Year : 1999
Volume : 9
Issue : 4
First Page : 589
Last Page : 594
Authors : Vuligonda V, Garst ME, Chandraratna RA.
Abstract : Retinoid X Receptor (RXR) specific ligands are currently being investigated for the treatment of metabolic diseases such as type II diabetes. We report the synthesis of conformationally locked retinoids, which are potent RXR selective ligands, and the attempted synthesis of 9-cyclopropyl locked analogs of RA and 9-cis RA.
|
Inhibition of [3H]9-cis-RA binding to Retinoid X receptor RXR gamma
|
None
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells.
Year : 1996
Volume : 39
Issue : 14
First Page : 2659
Last Page : 2663
Authors : Zhang L, Nadzan AM, Heyman RA, Love DL, Mais DE, Croston G, Lamph WW, Boehm MF.
Abstract : Retinoic acid receptor (RAR) active retinoids have proven therapeutically useful for treating certain cancers and dermatological diseases. Herein, we describe the discovery of two new RAR active trienoic acid retinoids, (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10a, ALRT1550) and (2E,4E,6Z)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2, 4,6-trienoic acid (10b, LG100567). ALRT1550 is a RAR selective retinoid which exhibits exceptional potency in both competitive binding and cotransfection assays. Moreover, it is the most potent antiproliferative retinoid described to date and thus has implications for the treatment of certain cancers. LG100567 is a potent panagonist which activates both RARs and retinoid X receptors.
|
Binding affinity towards Retinoic acid receptor RXR-gamma by displacing 3.4 nM 3[H]-9-cis-RA
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and receptor binding affinity of conformationally restricted retinoic acid analogues
Year : 1997
Volume : 7
Issue : 17
First Page : 2313
Last Page : 2318
Authors : Wong MF, Repa JJ, Clagett-Dame M, Curley RW
|
Agonist activity for retinoic acid receptor RAR alpha in transcriptional activation assay
|
Homo sapiens
|
191.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Differential RXR & RAR activity of stilbene retinoid analogs bearing thiazole and imidazole carboxylic acids
Year : 1995
Volume : 5
Issue : 22
First Page : 2729
Last Page : 2734
Authors : Beard RL, Colon DF, Klein ES, Vorse KA, Chandraratna RA
|
Transcriptional activation of Retinoic acid receptor RAR alpha
|
Homo sapiens
|
102.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids.
Year : 1995
Volume : 38
Issue : 15
First Page : 2820
Last Page : 2829
Authors : Beard RL, Chandraratna RA, Colon DF, Gillett SJ, Henry E, Marler DK, Song T, Denys L, Garst ME, Arefieg T.
Abstract : Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.
|
Transcriptional activation in CV-1 cells expressing human Retinoic acid receptor RAR alpha
|
Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Inhibition of [3H]ATRA binding to human Retinoic acid receptor RAR alpha
|
Homo sapiens
|
93.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
Year : 2003
Volume : 13
Issue : 2
First Page : 261
Last Page : 264
Authors : Farmer LJ, Zhi L, Jeong S, Lamph WW, Osburn DL, Croston G, Flatten KS, Heyman RA, Nadzan AM.
Abstract : A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.
|
Inhibition of SCC-2 cell proliferation
|
Canis lupus familiaris
|
13.0
%
|
|
Journal : J. Med. Chem.
Title : Heteroarotinoids inhibit head and neck cancer cell lines in vitro and in vivo through both RAR and RXR retinoic acid receptors.
Year : 1999
Volume : 42
Issue : 21
First Page : 4434
Last Page : 4445
Authors : Zacheis D, Dhar A, Lu S, Madler MM, Klucik J, Brown CW, Liu S, Clement F, Subramanian S, Weerasekare GM, Berlin KD, Gold MA, Houck JR, Fountain KR, Benbrook DM.
Abstract : A class of less toxic retinoids, called heteroarotinoids, was evaluated for their molecular mechanism of growth inhibition of two head and neck squamous cell carcinoma (HNSCC) cell lines SCC-2 and SCC-38. A series of 14 heteroarotinoids were screened for growth inhibition activity in vitro. The two most active compounds, one that contained an oxygen heteroatom (6) and the other a sulfur heteroatom (16), were evaluated in a xenograph model of tumor establishment in nude mice. Five days after subcutaneous injection of 10(7) SCC-38 cells, groups of 5 nu/nu mice were gavaged daily (5 days/week for 4 weeks) with 20 mg/kg/day of all-trans-retinoic acid (t-RA, 1), 10 mg/kg/day of 6, 10 mg/kg/day of 16, or sesame oil. After a few days, the dose of t-RA (1) was decreased to 10 mg/kg/day to alleviate the side effects of eczema and bone fracture. No significant toxic effects were observed in the heteroarotinoid groups. All three retinoids caused a statistically significant reduction in tumor size as determined by the Student t-test (P < 0. 05). Complete tumor regression was noted in 3 of 5 mice treated with t-RA (1), 4 of 5 mice treated with 16, 1 of 5 mice treated with 6, and 1 of 5 mice treated with sesame oil. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine that the expression levels of RARalpha, RXRalpha, and RXRbeta were similar in the two cell lines, while RARbeta expression was higher in SCC-2 over SCC-38, and RARgamma expression was higher in SCC-38 over SCC-2. Receptor cotransfection assays in CV-1 cells demonstrated that 16 was a potent activator of both RAR and RXR receptors, while 6 was selective for the RXR receptors. Transient cotransfection assays in CV-1 cells using an AP-1 responsive reporter plasmid demonstrated that t-RA (1), 6, and 16 each inhibited AP-1-driven transcription in this cell line. In conclusion, the growth inhibition activity of the RXR-selective 6 and the more potent growth inhibition activity of the RAR/RXR pan-agonist 16 implicate both RARs and RXRs in the molecular mechanism of retinoid growth inhibition. Moreover, the chemoprevention activity and the lack of toxicity of heteroarotinoids demonstrate their clinical potential in head and neck cancer chemoprevention.
|
Percent of growth inhibition of Cell line SCC-2(Head and Neck) by the compound
|
Homo sapiens
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
Year : 1999
Volume : 42
Issue : 18
First Page : 3602
Last Page : 3614
Authors : Dhar A, Liu S, Klucik J, Berlin KD, Madler MM, Lu S, Ivey RT, Zacheis D, Brown CW, Nelson EC, Birckbichler PJ, Benbrook DM.
Abstract : Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.
|
Inhibition of SCC-38 cell proliferation
|
Canis lupus familiaris
|
10.0
%
|
|
Journal : J. Med. Chem.
Title : Heteroarotinoids inhibit head and neck cancer cell lines in vitro and in vivo through both RAR and RXR retinoic acid receptors.
Year : 1999
Volume : 42
Issue : 21
First Page : 4434
Last Page : 4445
Authors : Zacheis D, Dhar A, Lu S, Madler MM, Klucik J, Brown CW, Liu S, Clement F, Subramanian S, Weerasekare GM, Berlin KD, Gold MA, Houck JR, Fountain KR, Benbrook DM.
Abstract : A class of less toxic retinoids, called heteroarotinoids, was evaluated for their molecular mechanism of growth inhibition of two head and neck squamous cell carcinoma (HNSCC) cell lines SCC-2 and SCC-38. A series of 14 heteroarotinoids were screened for growth inhibition activity in vitro. The two most active compounds, one that contained an oxygen heteroatom (6) and the other a sulfur heteroatom (16), were evaluated in a xenograph model of tumor establishment in nude mice. Five days after subcutaneous injection of 10(7) SCC-38 cells, groups of 5 nu/nu mice were gavaged daily (5 days/week for 4 weeks) with 20 mg/kg/day of all-trans-retinoic acid (t-RA, 1), 10 mg/kg/day of 6, 10 mg/kg/day of 16, or sesame oil. After a few days, the dose of t-RA (1) was decreased to 10 mg/kg/day to alleviate the side effects of eczema and bone fracture. No significant toxic effects were observed in the heteroarotinoid groups. All three retinoids caused a statistically significant reduction in tumor size as determined by the Student t-test (P < 0. 05). Complete tumor regression was noted in 3 of 5 mice treated with t-RA (1), 4 of 5 mice treated with 16, 1 of 5 mice treated with 6, and 1 of 5 mice treated with sesame oil. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine that the expression levels of RARalpha, RXRalpha, and RXRbeta were similar in the two cell lines, while RARbeta expression was higher in SCC-2 over SCC-38, and RARgamma expression was higher in SCC-38 over SCC-2. Receptor cotransfection assays in CV-1 cells demonstrated that 16 was a potent activator of both RAR and RXR receptors, while 6 was selective for the RXR receptors. Transient cotransfection assays in CV-1 cells using an AP-1 responsive reporter plasmid demonstrated that t-RA (1), 6, and 16 each inhibited AP-1-driven transcription in this cell line. In conclusion, the growth inhibition activity of the RXR-selective 6 and the more potent growth inhibition activity of the RAR/RXR pan-agonist 16 implicate both RARs and RXRs in the molecular mechanism of retinoid growth inhibition. Moreover, the chemoprevention activity and the lack of toxicity of heteroarotinoids demonstrate their clinical potential in head and neck cancer chemoprevention.
|
Percent of growth inhibition of Cell line SCC-38(Head and Neck) by the compound
|
Homo sapiens
|
24.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
Year : 1999
Volume : 42
Issue : 18
First Page : 3602
Last Page : 3614
Authors : Dhar A, Liu S, Klucik J, Berlin KD, Madler MM, Lu S, Ivey RT, Zacheis D, Brown CW, Nelson EC, Birckbichler PJ, Benbrook DM.
Abstract : Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.
|
Percent of growth inhibition of Cell line SW954 (Vulvar) by the compound
|
Homo sapiens
|
35.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
Year : 1999
Volume : 42
Issue : 18
First Page : 3602
Last Page : 3614
Authors : Dhar A, Liu S, Klucik J, Berlin KD, Madler MM, Lu S, Ivey RT, Zacheis D, Brown CW, Nelson EC, Birckbichler PJ, Benbrook DM.
Abstract : Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.
|
Percent of growth inhibition of Cell line SW962 (Vulvar) by the compound
|
Homo sapiens
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
Year : 1999
Volume : 42
Issue : 18
First Page : 3602
Last Page : 3614
Authors : Dhar A, Liu S, Klucik J, Berlin KD, Madler MM, Lu S, Ivey RT, Zacheis D, Brown CW, Nelson EC, Birckbichler PJ, Benbrook DM.
Abstract : Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.
|
Percent of growth inhibition of Cell line SKOV-3(Ovarian) by the compound
|
Homo sapiens
|
27.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
Year : 1999
Volume : 42
Issue : 18
First Page : 3602
Last Page : 3614
Authors : Dhar A, Liu S, Klucik J, Berlin KD, Madler MM, Lu S, Ivey RT, Zacheis D, Brown CW, Nelson EC, Birckbichler PJ, Benbrook DM.
Abstract : Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.
|
Percent of growth inhibition of Cell line SiHa (Cervix) by the compound
|
Homo sapiens
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
Year : 1999
Volume : 42
Issue : 18
First Page : 3602
Last Page : 3614
Authors : Dhar A, Liu S, Klucik J, Berlin KD, Madler MM, Lu S, Ivey RT, Zacheis D, Brown CW, Nelson EC, Birckbichler PJ, Benbrook DM.
Abstract : Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.
|
Inhibition of T47D retinoid sensitive breast carcinoma cell proliferation at 1 uM
|
Homo sapiens
|
35.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)phenyl]benzoic acid and heterocyclic-bridged analogues are novel retinoic acid receptor subtype and retinoid X receptor alpha agonists.
Year : 2000
Volume : 10
Issue : 12
First Page : 1311
Last Page : 1313
Authors : Dawson MI, Jong L, Hobbs PD, Xiao D, Feng KC, Chao WR, Pan C, Fontana JA, Zhang XK.
Abstract : Aromatic retinoids having a meta-substituted aromatic ring bridge, such as 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)phenyl]benzo ic acid and its 3,5-diaryl-substituted 4,5-dihydroisoxazole analogue, function as retinoid receptor panagonists by activating both retinoic acid and retinoid X receptors to induce gene transcription, and thereby provide novel scaffolds for retinoid drug development. Both classes of these ligand-inducible transcription factors are involved in mediating the inhibitory effects of retinoids on cancer cell growth.
|
Binding affinity towards cRAR-beta-2 receptor by displacing 0.82 nM 3[H]all-trans-RA
|
None
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and receptor binding affinity of conformationally restricted retinoic acid analogues
Year : 1997
Volume : 7
Issue : 17
First Page : 2313
Last Page : 2318
Authors : Wong MF, Repa JJ, Clagett-Dame M, Curley RW
|
Binding affinity towards cRAR-beta-2 receptor by displacing 1.1 nM 3[H]-9-cis-RA
|
None
|
0.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and receptor binding affinity of conformationally restricted retinoic acid analogues
Year : 1997
Volume : 7
Issue : 17
First Page : 2313
Last Page : 2318
Authors : Wong MF, Repa JJ, Clagett-Dame M, Curley RW
|
Inhibition of ZR-75-1 retinoid sensitive breast carcinoma cell proliferation at 1 uM
|
Homo sapiens
|
59.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)phenyl]benzoic acid and heterocyclic-bridged analogues are novel retinoic acid receptor subtype and retinoid X receptor alpha agonists.
Year : 2000
Volume : 10
Issue : 12
First Page : 1311
Last Page : 1313
Authors : Dawson MI, Jong L, Hobbs PD, Xiao D, Feng KC, Chao WR, Pan C, Fontana JA, Zhang XK.
Abstract : Aromatic retinoids having a meta-substituted aromatic ring bridge, such as 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)phenyl]benzo ic acid and its 3,5-diaryl-substituted 4,5-dihydroisoxazole analogue, function as retinoid receptor panagonists by activating both retinoic acid and retinoid X receptors to induce gene transcription, and thereby provide novel scaffolds for retinoid drug development. Both classes of these ligand-inducible transcription factors are involved in mediating the inhibitory effects of retinoids on cancer cell growth.
|
Inhibition of [3H]9-cis-retinoic acid binding to human retinoid X receptor alpha ligand-binding domain expressed in Escherichia coli
|
Homo sapiens
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Determinants of retinoid X receptor transcriptional antagonism.
Year : 2004
Volume : 47
Issue : 18
First Page : 4360
Last Page : 4372
Authors : Cavasotto CN, Liu G, James SY, Hobbs PD, Peterson VJ, Bhattacharya AA, Kolluri SK, Zhang XK, Leid M, Abagyan R, Liddington RC, Dawson MI.
Abstract : The synthesis and bioactivity of the retinoid X receptor (RXR) antagonist 4-[(3'-n-butyl-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2'-naphthalenyl)(cyclopropylidene)methyl]benzoic acid and several heteroatom-substituted analogues are described. Ligand design was based on the scaffold of the 3'-methyl RXR-selective agonist analogue and reports that 3'-n-propyl and longer n-alkyl groups conferred RXR antagonism. The transcriptional antagonism of the 3'-n-butyl analogue was demonstrated by its blockade of retinoic acid receptor (RAR) beta expression induced by the RXRalpha/peroxisome proliferator-activated receptor (PPAR) gamma heterodimer complexed with an RXRalpha agonist plus the PPARgamma agonist ciglitazone and the inhibition of 9-cis-RA-induced coactivator SRC-1a recruitment to RXRalpha. Receptor-ligand docking studies using full-atom flexible ligand and flexible receptor suggested that binding of the antagonist to the RXRalpha antagonist conformation was favored because the salt bridge that formed between the retinoid carboxylate and the RXRalpha helix H5 arginine-321 was far stronger than that formed on its binding to the agonist conformation. The antagonist also blocked activation of RAR subtypes alpha and beta by 9-cis-RA but not that of RARgamma.
|
Dissociation constant for Retinoid X receptor alpha
|
Homo sapiens
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Ligand recognition by RAR and RXR receptors: binding and selectivity.
Year : 2005
Volume : 48
Issue : 20
First Page : 6212
Last Page : 6219
Authors : Sussman F, de Lera AR.
Abstract : Fundamental biological functions, most notably embriogenesis, cell growth, cell differentiation, and cell apoptosis, are in part regulated by a complex genomic network that starts with the binding (and activation) of retinoids to their cognate receptors, members of the superfamily of nuclear receptors. We have studied ligand recognition of retinoic receptors (RXRalpha and RARgamma) using a molecular-mechanics-based docking method. The protocol used in this work is able to rank the affinity of pairs of ligands for a single retinoid receptor, the highest values corresponding to those that adapt better to the shape of the binding site and generate the optimal set of electrostatic and apolar interactions with the receptor. Moreover, our studies shed light onto some of the energetic contributions to retinoid receptor ligand selectivity. In this regard we show that there is a difference in polarity between the binding site regions that anchor the carboxylate in RAR and RXR, which translates itself into large differences in the energy of interaction of both receptors with the same ligand. We observe that the latter energy change is canceled off by the solvation energy penalty upon binding. This energy compensation is borne out as well by experiments that address the effect of site-directed mutagenesis on ligand binding to RARgamma. The hypothesis that the difference in binding site polarity might be exploited to build RXR-selective ligands is tested with some compounds having a thiazolidinedione anchoring group.
|
Dissociation constant for Retinoic acid receptor gamma
|
Homo sapiens
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Ligand recognition by RAR and RXR receptors: binding and selectivity.
Year : 2005
Volume : 48
Issue : 20
First Page : 6212
Last Page : 6219
Authors : Sussman F, de Lera AR.
Abstract : Fundamental biological functions, most notably embriogenesis, cell growth, cell differentiation, and cell apoptosis, are in part regulated by a complex genomic network that starts with the binding (and activation) of retinoids to their cognate receptors, members of the superfamily of nuclear receptors. We have studied ligand recognition of retinoic receptors (RXRalpha and RARgamma) using a molecular-mechanics-based docking method. The protocol used in this work is able to rank the affinity of pairs of ligands for a single retinoid receptor, the highest values corresponding to those that adapt better to the shape of the binding site and generate the optimal set of electrostatic and apolar interactions with the receptor. Moreover, our studies shed light onto some of the energetic contributions to retinoid receptor ligand selectivity. In this regard we show that there is a difference in polarity between the binding site regions that anchor the carboxylate in RAR and RXR, which translates itself into large differences in the energy of interaction of both receptors with the same ligand. We observe that the latter energy change is canceled off by the solvation energy penalty upon binding. This energy compensation is borne out as well by experiments that address the effect of site-directed mutagenesis on ligand binding to RARgamma. The hypothesis that the difference in binding site polarity might be exploited to build RXR-selective ligands is tested with some compounds having a thiazolidinedione anchoring group.
|
Transactivation of Gal4-LBD fused mouse RXRalpha (218 to 467) transfected in african green monkey CV1 cells assessed as luciferase activity at after 6 hrs by Dual-light chemiluminescent assay
|
Mus musculus
|
200.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Highly twisted adamantyl arotinoids: synthesis, antiproliferative effects and RXR transactivation profiles.
Year : 2009
Volume : 44
Issue : 6
First Page : 2434
Last Page : 2446
Authors : Pérez-Rodríguez S, Ortiz MA, Pereira R, Rodríguez-Barrios F, de Lera AR, Piedrafita FJ.
Abstract : Retinoid-related molecules with an adamantyl group (adamantyl arotinoids) have been described with selective activities towards the retinoid receptors as agonists for NR1B2 and NR1B3 (RARbeta,gamma) (CD437, MX3350-1) or RAR antagonists (MX781) that induce growth arrest and apoptosis in cancer cells. Since these molecules induce apoptosis independently of RAR transactivation, we set up to synthesize novel analogs with impaired RAR binding. Here we describe adamantyl arotinoids with 2,2'-disubstituted biaryl rings prepared using the Suzuki coupling of the corresponding fragments. Those with cinnamic and naphthoic acid end groups showed significant antiproliferative activity in several cancer cell lines, and this effect correlated with the induction of apoptosis as measured by caspase activity. Strikingly, some of these compounds, whereas devoid of RAR binding capacity, were able to activate RXR.
|
Binding affinity to Nur77 Y453A mutant expressed in human BGC823 cells
|
Homo sapiens
|
810.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Cytosporone B is an agonist for nuclear orphan receptor Nur77.
Year : 2008
Volume : 4
Issue : 9
First Page : 548
Last Page : 556
Authors : Zhan Y, Du X, Chen H, Liu J, Zhao B, Huang D, Li G, Xu Q, Zhang M, Weimer BC, Chen D, Cheng Z, Zhang L, Li Q, Li S, Zheng Z, Song S, Huang Y, Ye Z, Su W, Lin SC, Shen Y, Wu Q.
Abstract : Nuclear orphan receptor Nur77 has important roles in many biological processes. However, a physiological ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing positive autoregulation in a Csn-B-dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biological effects were not observed in Nur77-null (Nr4a1-/-) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biological function.
|
Binding affinity to RXRalpha
|
None
|
240.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Cytosporone B is an agonist for nuclear orphan receptor Nur77.
Year : 2008
Volume : 4
Issue : 9
First Page : 548
Last Page : 556
Authors : Zhan Y, Du X, Chen H, Liu J, Zhao B, Huang D, Li G, Xu Q, Zhang M, Weimer BC, Chen D, Cheng Z, Zhang L, Li Q, Li S, Zheng Z, Song S, Huang Y, Ye Z, Su W, Lin SC, Shen Y, Wu Q.
Abstract : Nuclear orphan receptor Nur77 has important roles in many biological processes. However, a physiological ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing positive autoregulation in a Csn-B-dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biological effects were not observed in Nur77-null (Nr4a1-/-) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biological function.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
14.27
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
-2.78
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of KLF4-ER-mediated rat RK3E cell transformation after 3 weeks
|
Rattus norvegicus
|
110.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.
Year : 2014
Volume : 22
Issue : 1
First Page : 178
Last Page : 185
Authors : Desphande A, Xia G, Boerma LJ, Vines KK, Atigadda VR, Lobo-Ruppert S, Grubbs CJ, Moeinpour FL, Smith CD, Christov K, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.
|
Agonist activity at RXRalpha in rat RK3E cells assessed as transcriptional activation by luciferase reporter gene assay
|
Rattus norvegicus
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.
Year : 2014
Volume : 22
Issue : 1
First Page : 178
Last Page : 185
Authors : Desphande A, Xia G, Boerma LJ, Vines KK, Atigadda VR, Lobo-Ruppert S, Grubbs CJ, Moeinpour FL, Smith CD, Christov K, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.
|
Binding affinity to human RXRalpha ligand binding domain by fluorescence assay
|
Homo sapiens
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.
Year : 2014
Volume : 22
Issue : 1
First Page : 178
Last Page : 185
Authors : Desphande A, Xia G, Boerma LJ, Vines KK, Atigadda VR, Lobo-Ruppert S, Grubbs CJ, Moeinpour FL, Smith CD, Christov K, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.
|
Binding affinity to human RXR-alpha-ligand binding domain homodimers by fluorescence quenching method
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
Year : 2014
Volume : 57
Issue : 12
First Page : 5370
Last Page : 5380
Authors : Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
|
Agonist activity at Gal4-fused human RXR-alpha expressed in HEK293 cells assessed as receptor-mediated transcriptional activity treated 24 hrs after transfection measured 48 hrs post-transfection by dual luciferase reporter assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
Year : 2014
Volume : 57
Issue : 12
First Page : 5370
Last Page : 5380
Authors : Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
|
Agonist activity at RXR-alpha in rat R3KE cells infected with oncogene KLF4-ER assessed as inhibition of KLF4-mediated oncogenic transformation
|
Rattus norvegicus
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
Year : 2014
Volume : 57
Issue : 12
First Page : 5370
Last Page : 5380
Authors : Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
|
Anticancer activity against N-methylnitrosurea-induced mammary cancer in Sprague-Dawley rat assessed as decrease in proliferation index at 150 mg/kg administered through diet for 7 days by BrdU incorporation assay
|
Rattus norvegicus
|
56.0
%
|
|
Journal : J. Med. Chem.
Title : Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
Year : 2014
Volume : 57
Issue : 12
First Page : 5370
Last Page : 5380
Authors : Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
|
Agonist activity at human RXRalpha expressed in HEK293 cells by luciferase reporter gene assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt.
Year : 2014
Volume : 24
Issue : 22
First Page : 5265
Last Page : 5267
Authors : Gege C, Schlüter T, Hoffmann T.
Abstract : Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) is a key transcription factor for the development of Th17 cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently N-(5-(arylcarbonyl)thiazol-2-yl)amides were described as RORγt antagonists with in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) via oral administration. So far no selective small molecule ligands have been revealed for RORβ. We show, that one compound of this class, namely N-[5-(2-chloro-benzoyl)-4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (4) is a potent dual inverse agonist towards RORγt and RORβ devoid of activity to 18 other human nuclear receptors and thus can serve as chemical probe to deepen our understanding about RORβ and its biology.
|
Binding affinity to RXR (unknown origin)
|
Homo sapiens
|
9.0
nM
|
|
Journal : J Med Chem
Title : Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery.
Year : 2017
Volume : 60
Issue : 13
First Page : 5235
Last Page : 5266
Authors : Proschak E, Heitel P, Kalinowsky L, Merk D.
Abstract : Fatty acids beyond their role as an endogenous energy source and storage are increasingly considered as signaling molecules regulating various physiological effects in metabolism and inflammation. Accordingly, the molecular targets involved in formation and physiological activities of fatty acids hold significant therapeutic potential. A number of these fatty acid targets are addressed by some of the oldest and most widely used drugs such as cyclooxygenase inhibiting NSAIDs, whereas others remain unexploited. Compounds orthosterically binding to proteins that endogenously bind fatty acids are considered as fatty acid mimetics. On the basis of their structural resemblance, fatty acid mimetics constitute a family of bioactive compounds showing specific binding thermodynamics and following similar pharmacokinetic mechanisms. This perspective systematically evaluates targets for fatty acid mimetics, investigates their common structural characteristics, and highlights demands in their discovery and design. In summary, fatty acid mimetics share particularly favorable characteristics justifying the conclusion that their therapeutic potential vastly outweighs the challenges in their design.
|
Displacement of CU-6PMN from human RXRalpha LBD incubated for 2 hrs by fluorescence based assay
|
Homo sapiens
|
583.0
nM
|
|
Journal : J Med Chem
Title : Competitive Binding Assay with an Umbelliferone-Based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening.
Year : 2019
Volume : 62
Issue : 19
First Page : 8809
Last Page : 8818
Authors : Yamada S, Kawasaki M, Fujihara M, Watanabe M, Takamura Y, Takioku M, Nishioka H, Takeuchi Y, Makishima M, Motoyama T, Ito S, Tokiwa H, Nakano S, Kakuta H.
Abstract : Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration.
|
Agonist activity at human RXR-alpha
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : Discovery of 3α,7α,11β-Trihydroxy-6α-ethyl-5β-cholan-24-oic Acid (TC-100), a Novel Bile Acid as Potent and Highly Selective FXR Agonist for Enterohepatic Disorders.
Year : 2016
Volume : 59
Issue : 19
First Page : 9201
Last Page : 9214
Authors : Pellicciari R,Passeri D,De Franco F,Mostarda S,Filipponi P,Colliva C,Gadaleta RM,Franco P,Carotti A,Macchiarulo A,Roda A,Moschetta A,Gioiello A
Abstract : As a continuation of previous efforts in mapping functional hot spots on the bile acid scaffold, we here demonstrate that the introduction of a hydroxy group at the C11β position affords high selectivity for FXR. In particular, the synthesis and FXR/TGR5 activity of novel bile acids bearing different hydroxylation patterns at the C ring are reported and discussed from a structure-activity standpoint. The results obtained led us to discover the first bile acid derivative endowed with high potency and selectivity at the FXR receptor, 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (TC-100, 7) which also shows a remarkable physicochemical and pharmacological profile. Compound 7 combines the excellent physicochemical properties of hydrophilic bile acids such as ursodeoxycholic acid, with the distinct ability to specifically bind and regulate FXR activity in vivo, thus providing a bona fide novel therapeutic agent to treat enterohepatic disorders such as cholestasis, NASH, and inflammatory bowel disease.
|
Agonist activity at GST-tagged human RXR assessed as induction of biotinylated coactivator SRC-1 peptide recruitment measured after 2 hrs by streptavidin-conjugated AlphaScreen assay
|
Homo sapiens
|
46.9
nM
|
|
Journal : J Med Chem
Title : Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis.
Year : 2020
Volume : 63
Issue : 21
First Page : 12748
Last Page : 12772
Authors : Li J,Liu M,Li Y,Sun DD,Shu Z,Tan Q,Guo S,Xie R,Gao L,Ru H,Zang Y,Liu H,Li J,Zhou Y
Abstract : Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable in vivo efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.
|
Displacement of 6-(Ethyl-{5-isobutoxy-4-isopropyl-2-[(10-oxo-2,3,5,6-tetrahydro-1H,4H,10H-11-oxa-3a-aza-benzo[de]anthracene-9-carbonyl)-amino]-phenyl}-amino)-nicotinic acid from human RXRalpha-LBD by by fluorescence binding assay
|
Homo sapiens
|
478.0
nM
|
|
Journal : J Med Chem
Title : Convenient Retinoid X Receptor Binding Assay Based on Fluorescence Change of the Antagonist NEt-C343.
Year : 2021
Volume : 64
Issue : 1.0
First Page : 861
Last Page : 870
Authors : Yukawa-Takamatsu K,Wang Y,Watanabe M,Takamura Y,Fujihara M,Nakamura-Nakayama M,Yamada S,Kikuzawa S,Makishima M,Kawasaki M,Ito S,Nakano S,Kakuta H
Abstract : Retinoid X receptor (RXR) modulators (rexinoids) are considered to have therapeutic potential for multiple diseases, such as Alzheimer's disease and Parkinson's disease. To overcome various disadvantages of prior screening methods, we previously developed an RXR binding assay using a fluorescent RXR ligand, CU-6PMN (4). However, this ligand binds not only at the ligand-binding domain (LBD) but also at the dimer-dimer interface of hRXRα. Here, we present a new fluorescent RXR antagonist 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(11-oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinoline-10-carboxamido)phenyl)amino]nicotinic acid (NEt-C343, 7), which emits strong fluorescence only when bound to the RXR-LBD. It allows us to perform a rapid, simple, and nonhazardous binding assay that does not require bound/free separation and uses a standard plate reader. The obtained Ki values of known compounds were correlated with the Ki values obtained using the standard [H]9cis-retinoic acid assay. This assay should be useful for drug discovery as well as for research on endocrine disruptors, functional foods, and natural products.
