|
Binding affinity for estrogen receptor, by competition with [3H]estradiol
|
None
|
990.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer.
Year : 1996
Volume : 39
Issue : 18
First Page : 3461
Last Page : 3469
Authors : Akama T, Shida Y, Sugaya T, Ishida H, Gomi K, Kasai M.
Abstract : In the course of our search for new antitumor agents in breast cancer, novel amino-substituted flavone derivatives were synthesized and examined for antitumor activities. Among them, 5,4'-diaminoflavone and some of its congeners showed remarkable antiproliferative activity against the estrogen receptor (ER)-positive and estrogen-responsive human breast cancer cell line MCF-7. The activity was observed irrespective of the presence or absence of estrogen. The 5-aminoflavone derivatives (5-AFs) are not classical anti-estrogens because they did not compete with [3H]estradiol to bind the estrogen receptor. Moreover, 5-AFs showed antitumor activity highly selective to the ER-positive breast cancer cell line, and they showed no effects against the ER-negative human cancer cell lines HeLa S3, WiDr, and MDA-MB-453. Although the mechanism of their selective antitumor activity to ER-positive breast cancer cells is unclear, 5-AFs are expected to be a new type of antitumor agents in breast cancer.
|
Inhibition of epidermal growth factor (EGF) receptor from A431 cell membranes at 150 uM
|
Homo sapiens
|
63.0
%
|
|
Journal : J. Med. Chem.
Title : Structural studies on bioactive compounds. 23. Synthesis of polyhydroxylated 2-phenylbenzothiazoles and a comparison of their cytotoxicities and pharmacological properties with genistein and quercetin.
Year : 1994
Volume : 37
Issue : 11
First Page : 1689
Last Page : 1695
Authors : Stevens MF, McCall CJ, Lelieveld P, Alexander P, Richter A, Davies DE.
Abstract : A series of polyhydroxylated 2-phenylbenzothiazoles 3 has been prepared by demethylation of the precursor methoxylated 2-phenylbenzothiazoles 9. The key step in the construction of the benzothiazole nucleus involves a Jacobson cyclization of methoxylated thiobenzanilides 8. The target compounds inhibit WiDr human colon tumor cells and MCF-7 human mammary tumor cells in vitro with IC50 values in the low micromolar range, but the activity against MCF-7 cells is not related to estrogen receptor-binding affinity. None of the compounds showed selective cytotoxicity against Abelson virus-transformed ANN-1 cells encoded with the pp120gag-abl tyrosine kinase compared with the parental 3T3 line. Compounds were only marginally inhibitory to the EGF receptor-associated protein tyrosine kinase from a membrane preparation of A431 cells. The most active compound was 4,6-dihydroxy-2-(4-hydroxyphenyl)benzothiazole (3b) which has the same overall hydroxyl substitution pattern as genistein (1a). The compounds were weakly cytotoxic for an EGF receptor, overexpressing cell line HN5, but when tested for differential toxicity against the EGF receptor tyrosine kinase or the PDGF receptor tyrosine kinase in a standard mitogenesis assay utilizing human fibroblasts, no discrimination was observed. In this assay, the compounds inhibited DNA synthesis when added to cells during S phase. This suggests that inhibition could not be interpreted in terms of tyrosine kinase inactivation but more likely as a relatively broad specificity for the ATP-binding domain of other kinases such as thymidine kinase.
|
Transcriptional potency (EC50) at Human estrogen receptor Beta
|
None
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues.
Year : 2001
Volume : 44
Issue : 24
First Page : 4230
Last Page : 4251
Authors : Meyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, Katzenellenbogen JA.
Abstract : Through an effort to develop novel ligands that have subtype selectivity for the estrogen receptors alpha (ERalpha) and beta (ERbeta), we have found that 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) acts as an agonist on both ER subtypes, but has a 70-fold higher relative binding affinity and 170-fold higher relative potency in transcription assays with ERbeta than with ERalpha. To investigate the ERbeta affinity- and potency-selective character of this DPN further, we prepared a series of DPN analogues in which both the ligand core and the aromatic rings were modified by the repositioning of phenolic hydroxy groups and by the addition of alkyl substituents and nitrile groups. We also prepared other series of DPN analogues in which the nitrile functionality was replaced with acetylene groups or polar functions, to mimic the linear geometry or polarity of the nitrile, respectively. To varying degrees, all of the analogues show preferential binding affinity for ERbeta (i.e., they are ERbeta affinity-selective), and many, but not all of them, are also more potent in activating transcription through ERbeta than through ERalpha (i.e., they are ERbeta potency-selective). meso-2,3-Bis(4-hydroxyphenyl)succinonitrile and dl-2,3-bis(4-hydroxyphenyl)succinonitrile are among the highest ERbeta affinity-selective ligands, and they have an ERbeta potency selectivity that is equivalent to that of DPN. The acetylene analogues have higher binding affinities but somewhat lower selectivities than their nitrile counterparts. The polar analogues have lower affinities, and only the fluorinated polar analogues have substantial affinity selectivities. This study suggests that, in this series of ligands, the nitrile functionality is critical to ERbeta selectivity because it provides the optimal combination of linear geometry and polarity. Furthermore, the addition of a second nitrile group beta to the nitrile in DPN or the addition of a methyl substitutent at an ortho position on the beta-aromatic ring increases the affinity and selectivity of these compounds for ERbeta. These ERbeta-selective compounds may prove to be valuable tools in understanding the differences in structure and biological function of ERalpha and ERbeta.
|
Ability to activate estrogen receptor 1-mediated transcription.
|
None
|
950.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationship of 3-arylbenzoxazines as selective estrogen receptor beta agonists.
Year : 2004
Volume : 14
Issue : 9
First Page : 2327
Last Page : 2330
Authors : Yang W, Wang Y, Ma Z, Golla R, Stouch T, Seethala R, Johnson S, Zhou R, Güngör T, Feyen JH, Dickson JK.
Abstract : A series of 3-aryl-7-hydroxybenzoxazine analogues have been prepared and evaluated as ligands for the two estrogen receptor subtypes (ERalpha and ERbeta). From the radioligand binding assay, compounds with more than a 10-fold binding selectivity toward the ERbeta subtype have been identified. These compounds have also been shown to be potent full agonists in the functional assay by activation of ERE promoted transcription, with the best compound being 20-fold more potent than genistein.
|
Activation of estrogen response element in HeLa cells stably transfected with human Estrogen receptor alpha.
|
None
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward selective ERbeta agonists for central nervous system disorders: synthesis and characterization of aryl benzthiophenes.
Year : 2002
Volume : 45
Issue : 7
First Page : 1399
Last Page : 1401
Authors : Schopfer U, Schoeffter P, Bischoff SF, Nozulak J, Feuerbach D, Floersheim P.
Abstract : In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these compounds could lead to drugs able to separate the beneficial effects of estrogens on mood, learning, and memory from side effects such as the stimulation of endometrial and breast cancer.
|
Binding affinity against human estrogen receptor alpha in competitive binding assay
|
None
|
92.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 1: The discovery of flavanoids with subtype selectivity.
Year : 2004
Volume : 14
Issue : 6
First Page : 1417
Last Page : 1421
Authors : Chen HY, Dykstra KD, Birzin ET, Frisch K, Chan W, Yang YT, Mosley RT, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A class of flavanoids exhibiting a high degree of selectivity for ERalpha over ERbeta has been discovered. The most active analogue 6 was found to be 66-fold ERalpha-selective and demonstrated uterine estradiol antagonism.
|
Binding affinity towards human estrogen receptor alpha(ERalpha)
|
None
|
395.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Constrained phytoestrogens and analogues as ERbeta selective ligands.
Year : 2003
Volume : 13
Issue : 14
First Page : 2399
Last Page : 2403
Authors : Miller CP, Collini MD, Harris HA.
Abstract : A new series of ERbeta (ERbeta) selective ligands has been prepared. One of the compounds 6, structurally related to the phytoestrogen apigenin 4, displays a binding preference for ERbeta over ERalpha of over 40-fold. In addition to its binding selectivity, 6 was able to potently induce metallothionein (an ERbeta specific response in human SAOS-2 cells) while demonstrating low potency in an ERalpha dependant ERE-tk luciferase assay in MCF-7 cells. Such receptor and cell selectivity could make 6 a useful molecular probe for better understanding the role of ERbeta in mammalian physiology.
|
Inhibition of binding of 17 beta-estradiol to human Estrogen receptor alpha
|
None
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phytoestrogens from the roots of Polygonum cuspidatum (Polygonaceae): structure-requirement of hydroxyanthraquinones for estrogenic activity.
Year : 2001
Volume : 11
Issue : 14
First Page : 1839
Last Page : 1842
Authors : Matsuda H, Shimoda H, Morikawa T, Yoshikawa M.
Abstract : The methanolic extract from the roots of Polygonum (P.) cuspidatum was found to enhance cell proliferation at 30 or 100 microg/mL in MCF-7, an estrogen-sensitive cell line. By bioassay-guided separation from P. cuspidatum with the most potent activity, emodin and emodin 8-O-beta-D-glucopyranoside were isolated as active principles. The methanolic extracts from Polygonum, Cassia, Aloe, and Rheum species, which were known to contain anthraquinones, also showed the MCF-7 proliferation. As a result of the evaluation of various anthraquinones from plant sources and synthetic anthraquinones, aloe-emodin, chrysophanol, chrysophanol 8-O-beta-D-glucopyranoside, and 1,8-dihydroxyanthraquinone showed weak activity. On the other hand, alizalin and 2,6-dihydroxyanthraquinone as well as emodin having the 2- and/or 6-hydroxyl groups showed potent activity. These results show that the unchelated hydroxyl group is essential for strong activity. Emodin and 2,6-dihydroxyanthraquinone also inhibited 17beta-estradiol binding to human estrogen receptors (ERs) with K(i) values of 0.77 and 0.31microM for ERalpha and 1.5 and 0.69 microM for ERbeta. These findings indicate that hydroxyanthraquinones such as emodin are phytoestrogens with an affinity to human estrogen receptors.
|
Ability to activate estrogen receptor 2-mediated transcription.
|
None
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationship of 3-arylbenzoxazines as selective estrogen receptor beta agonists.
Year : 2004
Volume : 14
Issue : 9
First Page : 2327
Last Page : 2330
Authors : Yang W, Wang Y, Ma Z, Golla R, Stouch T, Seethala R, Johnson S, Zhou R, Güngör T, Feyen JH, Dickson JK.
Abstract : A series of 3-aryl-7-hydroxybenzoxazine analogues have been prepared and evaluated as ligands for the two estrogen receptor subtypes (ERalpha and ERbeta). From the radioligand binding assay, compounds with more than a 10-fold binding selectivity toward the ERbeta subtype have been identified. These compounds have also been shown to be potent full agonists in the functional assay by activation of ERE promoted transcription, with the best compound being 20-fold more potent than genistein.
|
Activation of estrogen response element in HeLa cells stably transfected with human Estrogen receptor beta.
|
None
|
4.1
nM
|
|
Journal : J. Med. Chem.
Title : Toward selective ERbeta agonists for central nervous system disorders: synthesis and characterization of aryl benzthiophenes.
Year : 2002
Volume : 45
Issue : 7
First Page : 1399
Last Page : 1401
Authors : Schopfer U, Schoeffter P, Bischoff SF, Nozulak J, Feuerbach D, Floersheim P.
Abstract : In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these compounds could lead to drugs able to separate the beneficial effects of estrogens on mood, learning, and memory from side effects such as the stimulation of endometrial and breast cancer.
|
Agonist activity in transcriptional activation assay in SH-SY5Y neuroblastoma cells expressing Estrogen receptor beta
|
Homo sapiens
|
1.7
nM
|
|
Journal : J. Med. Chem.
Title : Toward selective ERbeta agonists for central nervous system disorders: synthesis and characterization of aryl benzthiophenes.
Year : 2002
Volume : 45
Issue : 7
First Page : 1399
Last Page : 1401
Authors : Schopfer U, Schoeffter P, Bischoff SF, Nozulak J, Feuerbach D, Floersheim P.
Abstract : In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these compounds could lead to drugs able to separate the beneficial effects of estrogens on mood, learning, and memory from side effects such as the stimulation of endometrial and breast cancer.
|
Inhibition of [3H]17-beta-estradiol binding to human recombinant Estrogen receptor beta.
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward selective ERbeta agonists for central nervous system disorders: synthesis and characterization of aryl benzthiophenes.
Year : 2002
Volume : 45
Issue : 7
First Page : 1399
Last Page : 1401
Authors : Schopfer U, Schoeffter P, Bischoff SF, Nozulak J, Feuerbach D, Floersheim P.
Abstract : In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these compounds could lead to drugs able to separate the beneficial effects of estrogens on mood, learning, and memory from side effects such as the stimulation of endometrial and breast cancer.
|
Binding affinity against human estrogen receptor beta (ER beta) in competitive binding assay
|
None
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 1: The discovery of flavanoids with subtype selectivity.
Year : 2004
Volume : 14
Issue : 6
First Page : 1417
Last Page : 1421
Authors : Chen HY, Dykstra KD, Birzin ET, Frisch K, Chan W, Yang YT, Mosley RT, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A class of flavanoids exhibiting a high degree of selectivity for ERalpha over ERbeta has been discovered. The most active analogue 6 was found to be 66-fold ERalpha-selective and demonstrated uterine estradiol antagonism.
|
Binding affinity towards estrogen receptor beta by [3H]17-beta-estradiol displacement.
|
None
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationship of 3-arylbenzoxazines as selective estrogen receptor beta agonists.
Year : 2004
Volume : 14
Issue : 9
First Page : 2327
Last Page : 2330
Authors : Yang W, Wang Y, Ma Z, Golla R, Stouch T, Seethala R, Johnson S, Zhou R, Güngör T, Feyen JH, Dickson JK.
Abstract : A series of 3-aryl-7-hydroxybenzoxazine analogues have been prepared and evaluated as ligands for the two estrogen receptor subtypes (ERalpha and ERbeta). From the radioligand binding assay, compounds with more than a 10-fold binding selectivity toward the ERbeta subtype have been identified. These compounds have also been shown to be potent full agonists in the functional assay by activation of ERE promoted transcription, with the best compound being 20-fold more potent than genistein.
|
Binding affinity towards human estrogen receptor beta (ERbeta)
|
None
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Constrained phytoestrogens and analogues as ERbeta selective ligands.
Year : 2003
Volume : 13
Issue : 14
First Page : 2399
Last Page : 2403
Authors : Miller CP, Collini MD, Harris HA.
Abstract : A new series of ERbeta (ERbeta) selective ligands has been prepared. One of the compounds 6, structurally related to the phytoestrogen apigenin 4, displays a binding preference for ERbeta over ERalpha of over 40-fold. In addition to its binding selectivity, 6 was able to potently induce metallothionein (an ERbeta specific response in human SAOS-2 cells) while demonstrating low potency in an ERalpha dependant ERE-tk luciferase assay in MCF-7 cells. Such receptor and cell selectivity could make 6 a useful molecular probe for better understanding the role of ERbeta in mammalian physiology.
|
Inhibition of binding of 17 beta-estradiol to human Estrogen receptor beta
|
None
|
83.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phytoestrogens from the roots of Polygonum cuspidatum (Polygonaceae): structure-requirement of hydroxyanthraquinones for estrogenic activity.
Year : 2001
Volume : 11
Issue : 14
First Page : 1839
Last Page : 1842
Authors : Matsuda H, Shimoda H, Morikawa T, Yoshikawa M.
Abstract : The methanolic extract from the roots of Polygonum (P.) cuspidatum was found to enhance cell proliferation at 30 or 100 microg/mL in MCF-7, an estrogen-sensitive cell line. By bioassay-guided separation from P. cuspidatum with the most potent activity, emodin and emodin 8-O-beta-D-glucopyranoside were isolated as active principles. The methanolic extracts from Polygonum, Cassia, Aloe, and Rheum species, which were known to contain anthraquinones, also showed the MCF-7 proliferation. As a result of the evaluation of various anthraquinones from plant sources and synthetic anthraquinones, aloe-emodin, chrysophanol, chrysophanol 8-O-beta-D-glucopyranoside, and 1,8-dihydroxyanthraquinone showed weak activity. On the other hand, alizalin and 2,6-dihydroxyanthraquinone as well as emodin having the 2- and/or 6-hydroxyl groups showed potent activity. These results show that the unchelated hydroxyl group is essential for strong activity. Emodin and 2,6-dihydroxyanthraquinone also inhibited 17beta-estradiol binding to human estrogen receptors (ERs) with K(i) values of 0.77 and 0.31microM for ERalpha and 1.5 and 0.69 microM for ERbeta. These findings indicate that hydroxyanthraquinones such as emodin are phytoestrogens with an affinity to human estrogen receptors.
|
Inhibition of binding of 17 beta-estradiol to human Estrogen receptor beta
|
None
|
24.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phytoestrogens from the roots of Polygonum cuspidatum (Polygonaceae): structure-requirement of hydroxyanthraquinones for estrogenic activity.
Year : 2001
Volume : 11
Issue : 14
First Page : 1839
Last Page : 1842
Authors : Matsuda H, Shimoda H, Morikawa T, Yoshikawa M.
Abstract : The methanolic extract from the roots of Polygonum (P.) cuspidatum was found to enhance cell proliferation at 30 or 100 microg/mL in MCF-7, an estrogen-sensitive cell line. By bioassay-guided separation from P. cuspidatum with the most potent activity, emodin and emodin 8-O-beta-D-glucopyranoside were isolated as active principles. The methanolic extracts from Polygonum, Cassia, Aloe, and Rheum species, which were known to contain anthraquinones, also showed the MCF-7 proliferation. As a result of the evaluation of various anthraquinones from plant sources and synthetic anthraquinones, aloe-emodin, chrysophanol, chrysophanol 8-O-beta-D-glucopyranoside, and 1,8-dihydroxyanthraquinone showed weak activity. On the other hand, alizalin and 2,6-dihydroxyanthraquinone as well as emodin having the 2- and/or 6-hydroxyl groups showed potent activity. These results show that the unchelated hydroxyl group is essential for strong activity. Emodin and 2,6-dihydroxyanthraquinone also inhibited 17beta-estradiol binding to human estrogen receptors (ERs) with K(i) values of 0.77 and 0.31microM for ERalpha and 1.5 and 0.69 microM for ERbeta. These findings indicate that hydroxyanthraquinones such as emodin are phytoestrogens with an affinity to human estrogen receptors.
|
Inhibition of 5-HIAA formation in isolated Hamster Liver Mitochondria at 0.3 uM.
|
Cricetulus griseus
|
31.3
%
|
|
Journal : J. Med. Chem.
Title : The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of daidzin.
Year : 2000
Volume : 43
Issue : 22
First Page : 4169
Last Page : 4179
Authors : Rooke N, Li DJ, Li J, Keung WM.
Abstract : Recent studies showed that daidzin suppresses ethanol intake in ethanol-preferring laboratory animals. In vitro, it potently and selectively inhibits the mitochondrial aldehyde dehydrogenase (ALDH-2). Further, it inhibits the conversion of monoamines such as serotonin (5-HT) and dopamine (DA) into their respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in isolated hamster or rat liver mitochondria. Studies on the suppression of ethanol intake and inhibition of 5-HIAA (or DOPAC) formation by six structural analogues of daidzin suggested a potential link between these two activities. This, together with the finding that daidzin does not affect the rates of mitochondria-catalyzed oxidative deamination of these monoamines, raised the possibility that the ethanol intake-suppressive (antidipsotropic) action of daidzin is not mediated by the monoamines but rather by their reactive biogenic aldehyde intermediates such as 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or 3,4-dihydroxyphenylacetaldehyde (DOPAL) which accumulate in the presence of daidzin. To further evaluate this possibility, we synthesized more structural analogues of daidzin and tested and compared their antidipsotropic activities in Syrian golden hamsters with their effects on monoamine metabolism in isolated hamster liver mitochondria using 5-HT as the substrate. Effects of daidzin and its structural analogues on the activities of monoamine oxidase (MAO) and ALDH-2, the key enzymes involved in 5-HT metabolism in the mitochondria, were also examined. Results from these studies reveal a positive correlation between the antidipsotropic activities of these analogues and their abilities to increase 5-HIAL accumulation during 5-HT metabolism in isolated hamster liver mitochondria. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also potently inhibit MAO exhibit little, if any, antidipsotropic activity. These results, although inconclusive, are consistent with the hypothesis that daidzin may act via the mitochondrial MAO/ALDH pathway and that a biogenic aldehyde such as 5-HIAL may be important in mediating its antidipsotropic action.
|
Inhibition of 5-HIAA formation in isolated Hamster Liver Mitochondria at 0.9 uM.
|
Cricetulus griseus
|
65.0
%
|
|
Journal : J. Med. Chem.
Title : The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of daidzin.
Year : 2000
Volume : 43
Issue : 22
First Page : 4169
Last Page : 4179
Authors : Rooke N, Li DJ, Li J, Keung WM.
Abstract : Recent studies showed that daidzin suppresses ethanol intake in ethanol-preferring laboratory animals. In vitro, it potently and selectively inhibits the mitochondrial aldehyde dehydrogenase (ALDH-2). Further, it inhibits the conversion of monoamines such as serotonin (5-HT) and dopamine (DA) into their respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in isolated hamster or rat liver mitochondria. Studies on the suppression of ethanol intake and inhibition of 5-HIAA (or DOPAC) formation by six structural analogues of daidzin suggested a potential link between these two activities. This, together with the finding that daidzin does not affect the rates of mitochondria-catalyzed oxidative deamination of these monoamines, raised the possibility that the ethanol intake-suppressive (antidipsotropic) action of daidzin is not mediated by the monoamines but rather by their reactive biogenic aldehyde intermediates such as 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or 3,4-dihydroxyphenylacetaldehyde (DOPAL) which accumulate in the presence of daidzin. To further evaluate this possibility, we synthesized more structural analogues of daidzin and tested and compared their antidipsotropic activities in Syrian golden hamsters with their effects on monoamine metabolism in isolated hamster liver mitochondria using 5-HT as the substrate. Effects of daidzin and its structural analogues on the activities of monoamine oxidase (MAO) and ALDH-2, the key enzymes involved in 5-HT metabolism in the mitochondria, were also examined. Results from these studies reveal a positive correlation between the antidipsotropic activities of these analogues and their abilities to increase 5-HIAL accumulation during 5-HT metabolism in isolated hamster liver mitochondria. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also potently inhibit MAO exhibit little, if any, antidipsotropic activity. These results, although inconclusive, are consistent with the hypothesis that daidzin may act via the mitochondrial MAO/ALDH pathway and that a biogenic aldehyde such as 5-HIAL may be important in mediating its antidipsotropic action.
|
Inhibition of 5-HIAA formation in isolated Hamster Liver Mitochondria at 3 uM.
|
Cricetulus griseus
|
77.6
%
|
|
Journal : J. Med. Chem.
Title : The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of daidzin.
Year : 2000
Volume : 43
Issue : 22
First Page : 4169
Last Page : 4179
Authors : Rooke N, Li DJ, Li J, Keung WM.
Abstract : Recent studies showed that daidzin suppresses ethanol intake in ethanol-preferring laboratory animals. In vitro, it potently and selectively inhibits the mitochondrial aldehyde dehydrogenase (ALDH-2). Further, it inhibits the conversion of monoamines such as serotonin (5-HT) and dopamine (DA) into their respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in isolated hamster or rat liver mitochondria. Studies on the suppression of ethanol intake and inhibition of 5-HIAA (or DOPAC) formation by six structural analogues of daidzin suggested a potential link between these two activities. This, together with the finding that daidzin does not affect the rates of mitochondria-catalyzed oxidative deamination of these monoamines, raised the possibility that the ethanol intake-suppressive (antidipsotropic) action of daidzin is not mediated by the monoamines but rather by their reactive biogenic aldehyde intermediates such as 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or 3,4-dihydroxyphenylacetaldehyde (DOPAL) which accumulate in the presence of daidzin. To further evaluate this possibility, we synthesized more structural analogues of daidzin and tested and compared their antidipsotropic activities in Syrian golden hamsters with their effects on monoamine metabolism in isolated hamster liver mitochondria using 5-HT as the substrate. Effects of daidzin and its structural analogues on the activities of monoamine oxidase (MAO) and ALDH-2, the key enzymes involved in 5-HT metabolism in the mitochondria, were also examined. Results from these studies reveal a positive correlation between the antidipsotropic activities of these analogues and their abilities to increase 5-HIAL accumulation during 5-HT metabolism in isolated hamster liver mitochondria. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also potently inhibit MAO exhibit little, if any, antidipsotropic activity. These results, although inconclusive, are consistent with the hypothesis that daidzin may act via the mitochondrial MAO/ALDH pathway and that a biogenic aldehyde such as 5-HIAL may be important in mediating its antidipsotropic action.
|
Inhibition of 5-HIAA formation in isolated Hamster Liver Mitochondria at 9 uM.
|
Cricetulus griseus
|
96.8
%
|
|
Journal : J. Med. Chem.
Title : The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of daidzin.
Year : 2000
Volume : 43
Issue : 22
First Page : 4169
Last Page : 4179
Authors : Rooke N, Li DJ, Li J, Keung WM.
Abstract : Recent studies showed that daidzin suppresses ethanol intake in ethanol-preferring laboratory animals. In vitro, it potently and selectively inhibits the mitochondrial aldehyde dehydrogenase (ALDH-2). Further, it inhibits the conversion of monoamines such as serotonin (5-HT) and dopamine (DA) into their respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in isolated hamster or rat liver mitochondria. Studies on the suppression of ethanol intake and inhibition of 5-HIAA (or DOPAC) formation by six structural analogues of daidzin suggested a potential link between these two activities. This, together with the finding that daidzin does not affect the rates of mitochondria-catalyzed oxidative deamination of these monoamines, raised the possibility that the ethanol intake-suppressive (antidipsotropic) action of daidzin is not mediated by the monoamines but rather by their reactive biogenic aldehyde intermediates such as 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or 3,4-dihydroxyphenylacetaldehyde (DOPAL) which accumulate in the presence of daidzin. To further evaluate this possibility, we synthesized more structural analogues of daidzin and tested and compared their antidipsotropic activities in Syrian golden hamsters with their effects on monoamine metabolism in isolated hamster liver mitochondria using 5-HT as the substrate. Effects of daidzin and its structural analogues on the activities of monoamine oxidase (MAO) and ALDH-2, the key enzymes involved in 5-HT metabolism in the mitochondria, were also examined. Results from these studies reveal a positive correlation between the antidipsotropic activities of these analogues and their abilities to increase 5-HIAL accumulation during 5-HT metabolism in isolated hamster liver mitochondria. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also potently inhibit MAO exhibit little, if any, antidipsotropic activity. These results, although inconclusive, are consistent with the hypothesis that daidzin may act via the mitochondrial MAO/ALDH pathway and that a biogenic aldehyde such as 5-HIAL may be important in mediating its antidipsotropic action.
|
Inhibition of Hamster Liver mitochondrial Monoamine oxidase.
|
Cricetulus griseus
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of daidzin.
Year : 2000
Volume : 43
Issue : 22
First Page : 4169
Last Page : 4179
Authors : Rooke N, Li DJ, Li J, Keung WM.
Abstract : Recent studies showed that daidzin suppresses ethanol intake in ethanol-preferring laboratory animals. In vitro, it potently and selectively inhibits the mitochondrial aldehyde dehydrogenase (ALDH-2). Further, it inhibits the conversion of monoamines such as serotonin (5-HT) and dopamine (DA) into their respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in isolated hamster or rat liver mitochondria. Studies on the suppression of ethanol intake and inhibition of 5-HIAA (or DOPAC) formation by six structural analogues of daidzin suggested a potential link between these two activities. This, together with the finding that daidzin does not affect the rates of mitochondria-catalyzed oxidative deamination of these monoamines, raised the possibility that the ethanol intake-suppressive (antidipsotropic) action of daidzin is not mediated by the monoamines but rather by their reactive biogenic aldehyde intermediates such as 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or 3,4-dihydroxyphenylacetaldehyde (DOPAL) which accumulate in the presence of daidzin. To further evaluate this possibility, we synthesized more structural analogues of daidzin and tested and compared their antidipsotropic activities in Syrian golden hamsters with their effects on monoamine metabolism in isolated hamster liver mitochondria using 5-HT as the substrate. Effects of daidzin and its structural analogues on the activities of monoamine oxidase (MAO) and ALDH-2, the key enzymes involved in 5-HT metabolism in the mitochondria, were also examined. Results from these studies reveal a positive correlation between the antidipsotropic activities of these analogues and their abilities to increase 5-HIAL accumulation during 5-HT metabolism in isolated hamster liver mitochondria. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also potently inhibit MAO exhibit little, if any, antidipsotropic activity. These results, although inconclusive, are consistent with the hypothesis that daidzin may act via the mitochondrial MAO/ALDH pathway and that a biogenic aldehyde such as 5-HIAL may be important in mediating its antidipsotropic action.
|
Transcriptional potency (EC50) at Human estrogen receptor alpha
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues.
Year : 2001
Volume : 44
Issue : 24
First Page : 4230
Last Page : 4251
Authors : Meyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, Katzenellenbogen JA.
Abstract : Through an effort to develop novel ligands that have subtype selectivity for the estrogen receptors alpha (ERalpha) and beta (ERbeta), we have found that 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) acts as an agonist on both ER subtypes, but has a 70-fold higher relative binding affinity and 170-fold higher relative potency in transcription assays with ERbeta than with ERalpha. To investigate the ERbeta affinity- and potency-selective character of this DPN further, we prepared a series of DPN analogues in which both the ligand core and the aromatic rings were modified by the repositioning of phenolic hydroxy groups and by the addition of alkyl substituents and nitrile groups. We also prepared other series of DPN analogues in which the nitrile functionality was replaced with acetylene groups or polar functions, to mimic the linear geometry or polarity of the nitrile, respectively. To varying degrees, all of the analogues show preferential binding affinity for ERbeta (i.e., they are ERbeta affinity-selective), and many, but not all of them, are also more potent in activating transcription through ERbeta than through ERalpha (i.e., they are ERbeta potency-selective). meso-2,3-Bis(4-hydroxyphenyl)succinonitrile and dl-2,3-bis(4-hydroxyphenyl)succinonitrile are among the highest ERbeta affinity-selective ligands, and they have an ERbeta potency selectivity that is equivalent to that of DPN. The acetylene analogues have higher binding affinities but somewhat lower selectivities than their nitrile counterparts. The polar analogues have lower affinities, and only the fluorinated polar analogues have substantial affinity selectivities. This study suggests that, in this series of ligands, the nitrile functionality is critical to ERbeta selectivity because it provides the optimal combination of linear geometry and polarity. Furthermore, the addition of a second nitrile group beta to the nitrile in DPN or the addition of a methyl substitutent at an ortho position on the beta-aromatic ring increases the affinity and selectivity of these compounds for ERbeta. These ERbeta-selective compounds may prove to be valuable tools in understanding the differences in structure and biological function of ERalpha and ERbeta.
|
Binding affinity for human Estrogen receptor beta
|
Homo sapiens
|
98.7
nM
|
|
Binding affinity for human Estrogen receptor beta
|
Homo sapiens
|
98.7
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based virtual screening for plant-based ERbeta-selective ligands as potential preventative therapy against age-related neurodegenerative diseases.
Year : 2005
Volume : 48
Issue : 10
First Page : 3463
Last Page : 3466
Authors : Zhao L, Brinton RD.
Abstract : ERbeta has been associated with estrogen-induced promotion of memory function and neuronal survival. Based on the optimized complex structure of human ERbeta LBD bound with genistein, computer-aided structure-based virtual screening against a natural source chemical database was conducted to determine the occurrence of plant-based ERbeta-selective ligands. Twelve representative hits derived from database screening were assessed for their binding profiles to both ERs, three of which displayed over 100-fold binding selectivity to ERbeta over ERalpha.
|
Binding affinity for human Estrogen receptor beta
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 7-Substituted 2-phenyl-benzofurans as ER beta selective ligands.
Year : 2004
Volume : 14
Issue : 19
First Page : 4925
Last Page : 4929
Authors : Collini MD, Kaufman DH, Manas ES, Harris HA, Henderson RA, Xu ZB, Unwalla RJ, Miller CP.
Abstract : A series of 2-(4-hydroxy-phenyl)-benzofuran-5-ols with relatively lipophilic groups in the 7-position of the benzofuran was prepared and the affinity and selectivity for ER beta was measured. Many of the analogues were found to be potent and selective ER beta ligands. Additional modifications at the benzofuran 4-position as well as at the 3'-position of the 2-phenyl group were found to further increase selectivity. Such modifications led to compounds with <10 nM potency and >100-fold selectivity for ER beta.
|
Binding affinity for human Estrogen receptor alpha
|
Homo sapiens
|
395.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 7-Substituted 2-phenyl-benzofurans as ER beta selective ligands.
Year : 2004
Volume : 14
Issue : 19
First Page : 4925
Last Page : 4929
Authors : Collini MD, Kaufman DH, Manas ES, Harris HA, Henderson RA, Xu ZB, Unwalla RJ, Miller CP.
Abstract : A series of 2-(4-hydroxy-phenyl)-benzofuran-5-ols with relatively lipophilic groups in the 7-position of the benzofuran was prepared and the affinity and selectivity for ER beta was measured. Many of the analogues were found to be potent and selective ER beta ligands. Additional modifications at the benzofuran 4-position as well as at the 3'-position of the 2-phenyl group were found to further increase selectivity. Such modifications led to compounds with <10 nM potency and >100-fold selectivity for ER beta.
|
Inhibition of [3H]17-beta-estradiol binding to human estrogen receptor beta expressed in Escherichia coli
|
Homo sapiens
|
9.7
nM
|
|
Journal : J. Med. Chem.
Title : ERbeta ligands. 3. Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERbeta selectivity.
Year : 2005
Volume : 48
Issue : 12
First Page : 3953
Last Page : 3979
Authors : Mewshaw RE, Edsall RJ, Yang C, Manas ES, Xu ZB, Henderson RA, Keith JC, Harris HA.
Abstract : The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ERbeta were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ERbeta, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.
|
Inhibition of [3H]17-beta-estradiol binding to human estrogen receptor alpha expressed in Escherichia coli
|
Homo sapiens
|
395.0
nM
|
|
Journal : J. Med. Chem.
Title : ERbeta ligands. 3. Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERbeta selectivity.
Year : 2005
Volume : 48
Issue : 12
First Page : 3953
Last Page : 3979
Authors : Mewshaw RE, Edsall RJ, Yang C, Manas ES, Xu ZB, Henderson RA, Keith JC, Harris HA.
Abstract : The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ERbeta were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ERbeta, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.
|
Inhibitory concentration against human ER beta expressed in Escherichia coli was determined using [3H]17-beta-estradiol as radio ligand
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands.
Year : 2004
Volume : 47
Issue : 21
First Page : 5021
Last Page : 5040
Authors : Malamas MS, Manas ES, McDevitt RE, Gunawan I, Xu ZB, Collini MD, Miller CP, Dinh T, Henderson RA, Keith JC, Harris HA.
Abstract : New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
|
Inhibitory concentration against human ER alpha expressed in Escherichia coli was determined using [3H]17-beta-estradiol as radio ligand
|
Homo sapiens
|
395.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands.
Year : 2004
Volume : 47
Issue : 21
First Page : 5021
Last Page : 5040
Authors : Malamas MS, Manas ES, McDevitt RE, Gunawan I, Xu ZB, Collini MD, Miller CP, Dinh T, Henderson RA, Keith JC, Harris HA.
Abstract : New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
|
Binding affinity for human Estrogen receptor beta
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : ERbeta ligands. Part 4: Synthesis and structure-activity relationships of a series of 2-phenylquinoline derivatives.
Year : 2005
Volume : 15
Issue : 20
First Page : 4520
Last Page : 4525
Authors : Vu AT, Cohn ST, Manas ES, Harris HA, Mewshaw RE.
Abstract : A new class of estrogen receptor beta (ERbeta) ligands based on the 2-phenylquinoline scaffold was prepared. Several analogues with C4 substitution displayed high affinity (3-5 nM) and significant selectivity (up to 83-fold) for ERbeta. The best compound, 13b, was profiled as a selective partial agonist for ERbeta at 1 muM in a cell-based transcriptional assay. Uterine weight bioassay of 13b indicated no activation of ERalpha in vivo.
|
Binding affinity for human Estrogen receptor alpha
|
Homo sapiens
|
395.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : ERbeta ligands. Part 4: Synthesis and structure-activity relationships of a series of 2-phenylquinoline derivatives.
Year : 2005
Volume : 15
Issue : 20
First Page : 4520
Last Page : 4525
Authors : Vu AT, Cohn ST, Manas ES, Harris HA, Mewshaw RE.
Abstract : A new class of estrogen receptor beta (ERbeta) ligands based on the 2-phenylquinoline scaffold was prepared. Several analogues with C4 substitution displayed high affinity (3-5 nM) and significant selectivity (up to 83-fold) for ERbeta. The best compound, 13b, was profiled as a selective partial agonist for ERbeta at 1 muM in a cell-based transcriptional assay. Uterine weight bioassay of 13b indicated no activation of ERalpha in vivo.
|
Displacement of [3H]17beta-estradiol from recombinant human ERalpha expressed in 293T cells
|
Homo sapiens
|
29.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor beta selective ligands: discovery and SAR of novel heterocyclic ligands.
Year : 2005
Volume : 15
Issue : 24
First Page : 5562
Last Page : 5566
Authors : Chesworth R, Wessel MD, Heyden L, Mangano FM, Zawistoski M, Gegnas L, Galluzzo D, Lefker B, Cameron KO, Tickner J, Lu B, Castleberry TA, Petersen DN, Brault A, Perry P, Ng O, Owen TA, Pan L, Ke HZ, Brown TA, Thompson DD, DaSilva-Jardine P.
Abstract : A series of ligands with varying heterocyclic cores and substituents that display a range of selectivity's (up to >100x) for ER-beta over ER-alpha are reported.
|
Displacement of [3H]17beta-estradiol from recombinant human ERbeta expressed in 293T cells
|
Homo sapiens
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor beta selective ligands: discovery and SAR of novel heterocyclic ligands.
Year : 2005
Volume : 15
Issue : 24
First Page : 5562
Last Page : 5566
Authors : Chesworth R, Wessel MD, Heyden L, Mangano FM, Zawistoski M, Gegnas L, Galluzzo D, Lefker B, Cameron KO, Tickner J, Lu B, Castleberry TA, Petersen DN, Brault A, Perry P, Ng O, Owen TA, Pan L, Ke HZ, Brown TA, Thompson DD, DaSilva-Jardine P.
Abstract : A series of ligands with varying heterocyclic cores and substituents that display a range of selectivity's (up to >100x) for ER-beta over ER-alpha are reported.
|
Displacement of [3H]estrone from ER beta
|
Homo sapiens
|
61.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and characterization of 3-arylquinazolinone and 3-arylquinazolinethione derivatives as selective estrogen receptor beta modulators.
Year : 2006
Volume : 49
Issue : 8
First Page : 2440
Last Page : 2455
Authors : Güngör T, Chen Y, Golla R, Ma Z, Corte JR, Northrop JP, Bin B, Dickson JK, Stouch T, Zhou R, Johnson SE, Seethala R, Feyen JH.
Abstract : On the basis of the stucture of genistein, a new series of 3-arylquinazolines was prepared and tested for their estrogen receptor (ER) alpha and beta affinities. 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (1aa) acts as an agonist on both ER subtypes. It has 62-fold higher binding affinity [IC(50)(ERbeta) = 179 nM] and 38-fold higher functional potency in a transcription assay [EC(50)(ERbeta) = 76 nM] with ERbeta than with ERalpha, thus improving upon the selectivity of genistein. All of the analogues showed preferential binding affinity for ERbeta. Many are also more potent in activating transcription by ERbeta than by ERalpha. Transformation of the C=O functionality at position 4 into a C=S group provided 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinethione (1ba), which acts as an agonist on both ER subtypes but has 56-fold higher binding affinity for ERbeta over ERalpha [IC(50)(ERbeta) = 47 nM] and 215-fold higher potency in the transcription assay [EC(50)(ERbeta) = 13 nM]. These ERbeta-selective compounds may represent valuable tools in understanding the differences in structure and biological function of ERbeta and ERalpha.
|
Inhibition of ER beta-mediated transactivation of ERE in HeLa cell luciferase assay
|
Homo sapiens
|
73.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and characterization of 3-arylquinazolinone and 3-arylquinazolinethione derivatives as selective estrogen receptor beta modulators.
Year : 2006
Volume : 49
Issue : 8
First Page : 2440
Last Page : 2455
Authors : Güngör T, Chen Y, Golla R, Ma Z, Corte JR, Northrop JP, Bin B, Dickson JK, Stouch T, Zhou R, Johnson SE, Seethala R, Feyen JH.
Abstract : On the basis of the stucture of genistein, a new series of 3-arylquinazolines was prepared and tested for their estrogen receptor (ER) alpha and beta affinities. 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (1aa) acts as an agonist on both ER subtypes. It has 62-fold higher binding affinity [IC(50)(ERbeta) = 179 nM] and 38-fold higher functional potency in a transcription assay [EC(50)(ERbeta) = 76 nM] with ERbeta than with ERalpha, thus improving upon the selectivity of genistein. All of the analogues showed preferential binding affinity for ERbeta. Many are also more potent in activating transcription by ERbeta than by ERalpha. Transformation of the C=O functionality at position 4 into a C=S group provided 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinethione (1ba), which acts as an agonist on both ER subtypes but has 56-fold higher binding affinity for ERbeta over ERalpha [IC(50)(ERbeta) = 47 nM] and 215-fold higher potency in the transcription assay [EC(50)(ERbeta) = 13 nM]. These ERbeta-selective compounds may represent valuable tools in understanding the differences in structure and biological function of ERbeta and ERalpha.
|
Inhibition of ER beta-mediated transactivation of ERE in HeLa cell luciferase assay at 10 uM
|
Homo sapiens
|
956.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and characterization of 3-arylquinazolinone and 3-arylquinazolinethione derivatives as selective estrogen receptor beta modulators.
Year : 2006
Volume : 49
Issue : 8
First Page : 2440
Last Page : 2455
Authors : Güngör T, Chen Y, Golla R, Ma Z, Corte JR, Northrop JP, Bin B, Dickson JK, Stouch T, Zhou R, Johnson SE, Seethala R, Feyen JH.
Abstract : On the basis of the stucture of genistein, a new series of 3-arylquinazolines was prepared and tested for their estrogen receptor (ER) alpha and beta affinities. 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (1aa) acts as an agonist on both ER subtypes. It has 62-fold higher binding affinity [IC(50)(ERbeta) = 179 nM] and 38-fold higher functional potency in a transcription assay [EC(50)(ERbeta) = 76 nM] with ERbeta than with ERalpha, thus improving upon the selectivity of genistein. All of the analogues showed preferential binding affinity for ERbeta. Many are also more potent in activating transcription by ERbeta than by ERalpha. Transformation of the C=O functionality at position 4 into a C=S group provided 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinethione (1ba), which acts as an agonist on both ER subtypes but has 56-fold higher binding affinity for ERbeta over ERalpha [IC(50)(ERbeta) = 47 nM] and 215-fold higher potency in the transcription assay [EC(50)(ERbeta) = 13 nM]. These ERbeta-selective compounds may represent valuable tools in understanding the differences in structure and biological function of ERbeta and ERalpha.
|
Displacement of [3H]E2 from human recombinant ERbeta LBD by SPA
|
Homo sapiens
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Subtle side-chain modifications of the hop phytoestrogen 8-prenylnaringenin result in distinct agonist/antagonist activity profiles for estrogen receptors alpha and beta.
Year : 2006
Volume : 49
Issue : 25
First Page : 7357
Last Page : 7365
Authors : Roelens F, Heldring N, Dhooge W, Bengtsson M, Comhaire F, Gustafsson JA, Treuter E, De Keukeleire D.
Abstract : In search of therapeutic agents for estrogen-related pathologies, phytoestrogens are being extensively explored. In contrast to naringenin, 8-prenylnaringenin is a potent hop-derived estrogenic compound, highlighting the importance of the prenyl group for hormonal activity. We investigated the effects of substituting the prenyl group at C(8) with alkyl chains of varying lengths and branching patterns on estrogen receptor (ER) subtype ERalpha- and ERbeta-binding affinities and transcriptional activities. In addition, features of the ligand-induced receptor conformations were explored using a set of specific ER-binding peptides. The new 8-alkylnaringenins were found to span an activity spectrum ranging from full agonism to partial agonism to antagonism. Most strikingly, 8-(2,2-dimethylpropyl)naringenin exhibited full agonist character on ERalpha, but pronounced antagonist character on ERbeta. Knowledge on how ER-subtype-selective activities can be designed provides valuable information for future drug or tool compound discovery.
|
Inhibition of human LBD of of ERalpha
|
Homo sapiens
|
9.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor beta ligands: design and synthesis of new 2-phenyl-isoindole-1,3-diones.
Year : 2007
Volume : 17
Issue : 1
First Page : 118
Last Page : 122
Authors : Ullrich JW, Unwalla RJ, Singhaus RR, Harris HA, Mewshaw RE.
Abstract : The design, synthesis, and biological evaluation of the 2-phenyl-isoindole-1,3-diones will be discussed. Detailed modeling studies with X-ray support were used to understand the ligand binding orientation and observed selectivity.
|
Inhibition of human LBD of ERbeta
|
Homo sapiens
|
395.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor beta ligands: design and synthesis of new 2-phenyl-isoindole-1,3-diones.
Year : 2007
Volume : 17
Issue : 1
First Page : 118
Last Page : 122
Authors : Ullrich JW, Unwalla RJ, Singhaus RR, Harris HA, Mewshaw RE.
Abstract : The design, synthesis, and biological evaluation of the 2-phenyl-isoindole-1,3-diones will be discussed. Detailed modeling studies with X-ray support were used to understand the ligand binding orientation and observed selectivity.
|
Inhibition of human ERbeta by radioligand binding assay
|
Homo sapiens
|
9.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : ERbeta ligands. Part 5: synthesis and structure-activity relationships of a series of 4'-hydroxyphenyl-aryl-carbaldehyde oxime derivatives.
Year : 2007
Volume : 17
Issue : 4
First Page : 902
Last Page : 906
Authors : Mewshaw RE, Bowen SM, Harris HA, Xu ZB, Manas ES, Cohn ST.
Abstract : A series of 4'-hydroxyphenyl-aryl-carbaldehyde oximes (5b) was prepared and found to have high affinity (4nM) and modest selectivity (39-fold) for estrogen receptor-beta (ERbeta). Substitution of one of the core rings of the scaffold based around these novel ligands further expanded our knowledge in the quest toward achieving high affinity and selectivity for ERbeta. An X-ray co-crystal of structure 11 revealed that the oxime moiety was mimicking the C-ring of genistein, as previously predicted by SAR and docking studies.
|
Inhibition of human ERalpha by radioligand binding assay
|
Homo sapiens
|
395.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : ERbeta ligands. Part 5: synthesis and structure-activity relationships of a series of 4'-hydroxyphenyl-aryl-carbaldehyde oxime derivatives.
Year : 2007
Volume : 17
Issue : 4
First Page : 902
Last Page : 906
Authors : Mewshaw RE, Bowen SM, Harris HA, Xu ZB, Manas ES, Cohn ST.
Abstract : A series of 4'-hydroxyphenyl-aryl-carbaldehyde oximes (5b) was prepared and found to have high affinity (4nM) and modest selectivity (39-fold) for estrogen receptor-beta (ERbeta). Substitution of one of the core rings of the scaffold based around these novel ligands further expanded our knowledge in the quest toward achieving high affinity and selectivity for ERbeta. An X-ray co-crystal of structure 11 revealed that the oxime moiety was mimicking the C-ring of genistein, as previously predicted by SAR and docking studies.
|
Displacement of [3H]17beta-estradiol from recombinant human ERalpha
|
Homo sapiens
|
580.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Aza analogues of equol: novel ligands for estrogen receptor beta.
Year : 2007
Volume : 15
Issue : 17
First Page : 5828
Last Page : 5836
Authors : Chen W, Lin Z, Ning M, Yang C, Yan X, Xie Y, Shen X, Wang MW.
Abstract : 3-Aryl-tetrahydroquinolines, aza analogues of equol, are synthesized and evaluated for their binding properties to the estrogen receptors ERalpha and ERbeta. Several of these compounds exhibited binding selectivity for ER similar to that of genistein. Compounds 8c and 8d were found to have dual actions: antagonists for ERalpha and agonists for ERbeta in a yeast two-hybrid assay. These compounds have no estrogenic effects on the uterus and bone in vivo.
|
Displacement of [3H]17beta-estradiol from recombinant human ERbeta
|
Homo sapiens
|
6.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Aza analogues of equol: novel ligands for estrogen receptor beta.
Year : 2007
Volume : 15
Issue : 17
First Page : 5828
Last Page : 5836
Authors : Chen W, Lin Z, Ning M, Yang C, Yan X, Xie Y, Shen X, Wang MW.
Abstract : 3-Aryl-tetrahydroquinolines, aza analogues of equol, are synthesized and evaluated for their binding properties to the estrogen receptors ERalpha and ERbeta. Several of these compounds exhibited binding selectivity for ER similar to that of genistein. Compounds 8c and 8d were found to have dual actions: antagonists for ERalpha and agonists for ERbeta in a yeast two-hybrid assay. These compounds have no estrogenic effects on the uterus and bone in vivo.
|
Agonist activity at human ERalpha expressed in yeast AH109 by yeast two hybrid assay
|
Homo sapiens
|
810.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Aza analogues of equol: novel ligands for estrogen receptor beta.
Year : 2007
Volume : 15
Issue : 17
First Page : 5828
Last Page : 5836
Authors : Chen W, Lin Z, Ning M, Yang C, Yan X, Xie Y, Shen X, Wang MW.
Abstract : 3-Aryl-tetrahydroquinolines, aza analogues of equol, are synthesized and evaluated for their binding properties to the estrogen receptors ERalpha and ERbeta. Several of these compounds exhibited binding selectivity for ER similar to that of genistein. Compounds 8c and 8d were found to have dual actions: antagonists for ERalpha and agonists for ERbeta in a yeast two-hybrid assay. These compounds have no estrogenic effects on the uterus and bone in vivo.
|
Agonist activity at human ERbeta expressed in yeast AH109 by yeast two hybrid assay
|
Homo sapiens
|
28.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Aza analogues of equol: novel ligands for estrogen receptor beta.
Year : 2007
Volume : 15
Issue : 17
First Page : 5828
Last Page : 5836
Authors : Chen W, Lin Z, Ning M, Yang C, Yan X, Xie Y, Shen X, Wang MW.
Abstract : 3-Aryl-tetrahydroquinolines, aza analogues of equol, are synthesized and evaluated for their binding properties to the estrogen receptors ERalpha and ERbeta. Several of these compounds exhibited binding selectivity for ER similar to that of genistein. Compounds 8c and 8d were found to have dual actions: antagonists for ERalpha and agonists for ERbeta in a yeast two-hybrid assay. These compounds have no estrogenic effects on the uterus and bone in vivo.
|
Inhibition of invasion of human HT1080 cells at 3 uM after 24 hrs
|
Homo sapiens
|
5.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Inhibition of invasion of human HT1080 cells at 10 uM after 24 hrs
|
Homo sapiens
|
35.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Inhibition of invasion of human HT1080 cells at 30 uM after 24 hrs
|
Homo sapiens
|
43.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 3 uM after 24 hrs by MTT assay
|
Homo sapiens
|
-6.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 10 uM after 24 hrs by MTT assay
|
Homo sapiens
|
-1.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 30 uM after 24 hrs by MTT assay
|
Homo sapiens
|
12.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 3 uM after 48 hrs by MTT assay
|
Homo sapiens
|
3.8
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 10 uM after 48 hrs by MTT assay
|
Homo sapiens
|
9.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 30 uM after 48 hrs by MTT assay
|
Homo sapiens
|
25.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 3 uM after 72 hrs by MTT assay
|
Homo sapiens
|
-0.9
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 10 uM after 72 hrs by MTT assay
|
Homo sapiens
|
1.7
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 30 uM after 72 hrs by MTT assay
|
Homo sapiens
|
22.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 3 uM after 24 hrs by calcein-AM assay
|
Homo sapiens
|
2.8
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 10 uM after 24 hrs by calcein-AM assay
|
Homo sapiens
|
6.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 30 uM after 24 hrs by calcein-AM assay
|
Homo sapiens
|
17.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 3 uM after 48 hrs by calcein-AM assay
|
Homo sapiens
|
2.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 10 uM after 48 hrs by calcein-AM assay
|
Homo sapiens
|
5.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 30 uM after 48 hrs by calcein-AM assay
|
Homo sapiens
|
17.6
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 3 uM after 72 hrs by calcein-AM assay
|
Homo sapiens
|
1.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 10 uM after 72 hrs by calcein-AM assay
|
Homo sapiens
|
6.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Antiproliferative activity against human HT1080 cells at 30 uM after 72 hrs by calcein-AM assay
|
Homo sapiens
|
17.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Rotenoids and flavonoids with anti-invasion of HT1080, anti-proliferation of U937, and differentiation-inducing activity in HL-60 from Erycibe expansa.
Year : 2007
Volume : 15
Issue : 3
First Page : 1539
Last Page : 1546
Authors : Matsuda H, Yoshida K, Miyagawa K, Asao Y, Takayama S, Nakashima S, Xu F, Yoshikawa M.
Abstract : Principal rotenoids (deguelin, tephrosin, rotenone, and 12a-hydroxyrotenone) (3-30microM) isolated from the stems of Erycibe expansa significantly inhibited invasion of human fibrosarcoma HT1080 cells through Matrigel-coated filters and release of proMMPs-2 and 9. In addition, deguelin and tephrosin showed differentiation-inducing activity in human promyelocytic leukemia HL-60 cells. Furthermore, effects of various constituents isolated from the ethyl acetate-soluble fraction on proliferation of human leukemia U937 cells were examined. As a result, most of isoflavones and several flavans as well as rotenoids showed moderate or substantial anti-proliferative activities.
|
Inhibition of human ERalpha
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : ERbeta ligands. Part 6: 6H-Chromeno[4,3-b]quinolines as a new series of estrogen receptor beta-selective ligands.
Year : 2007
Volume : 17
Issue : 14
First Page : 4053
Last Page : 4056
Authors : Vu AT, Campbell AN, Harris HA, Unwalla RJ, Manas ES, Mewshaw RE.
Abstract : A new class of estrogen receptor beta (ERbeta) ligands based on the 6H-chromeno[4,3-b]quinoline scaffold has been prepared. Several C7-substituted analogues displayed high affinity and modest selectivity for ERbeta.
|
Inhibition of human ERbeta
|
Homo sapiens
|
395.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : ERbeta ligands. Part 6: 6H-Chromeno[4,3-b]quinolines as a new series of estrogen receptor beta-selective ligands.
Year : 2007
Volume : 17
Issue : 14
First Page : 4053
Last Page : 4056
Authors : Vu AT, Campbell AN, Harris HA, Unwalla RJ, Manas ES, Mewshaw RE.
Abstract : A new class of estrogen receptor beta (ERbeta) ligands based on the 6H-chromeno[4,3-b]quinoline scaffold has been prepared. Several C7-substituted analogues displayed high affinity and modest selectivity for ERbeta.
|
Growth inhibition of human KG1a cells at 5 uM after 48 hrs
|
Homo sapiens
|
10.0
%
|
|
Journal : J. Nat. Prod.
Title : Antileukemic activity of genistein, a major isoflavone present in soy products.
Year : 2008
Volume : 71
Issue : 1
First Page : 3
Last Page : 7
Authors : Raynal NJ, Momparler L, Charbonneau M, Momparler RL.
Abstract : Soy has been used in traditional medicine for the treatment of various diseases, including cancer. The isoflavones present in soy have been shown in animal models to have cancer-preventing activity. However, the therapeutic effects of isoflavones against cancer are still unclear. We have evaluated the in vitro and in vivo antileukemic activity of genistein (1), a major isoflavone present in soy. We observed that it produced a dose- and time-dependent antineoplastic activity against myeloid and lymphoid leukemic cell lines. In addition, genistein treatment of the leukemic cells reactivated tumor suppressor genes that were silenced by aberrant DNA methylation. A genistein-enriched diet produced a moderate, but significant, antileukemic effect in mice. The limited extent of this in vivo response may have been due to the rapid metabolic inactivation of genistein in mice. Due to the longer half-life of genistein in humans, a soy-enriched diet has the potential to produce plasma levels of this isoflavone in the range of the concentrations used in vitro that produced an antileukemic activity.
|
Inhibition of human DNA topoisomerase 2 catalytic domain-mediated knotted bacteriophage P4Virl dell0 DNA unknotting by agarose gel electrophoresis
|
Homo sapiens
|
30.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Flavonoids as DNA topoisomerase antagonists and poisons: structure-activity relationships.
Year : 1995
Volume : 58
Issue : 2
First Page : 217
Last Page : 225
Authors : Constantinou A, Mehta R, Runyan C, Rao K, Vaughan A, Moon R.
Abstract : Selected flavonoids were tested for their ability to inhibit the catalytic activity of DNA topoisomerase (topo) I and II. Myricetin, quercetin, fisetin, and morin were found to inhibit both enzymes, while phloretin, kaempferol, and 4',6,7-trihydroxyisoflavone inhibited topo II without inhibiting topo I. Flavonoids demonstrating potent topo I and II inhibition required hydroxyl group substitution at the C-3, C-7, C-3', and C-4' positions and also required a keto group at C-4. Additional B-ring hydroxylation enhanced flavonoid topo I inhibitory action. A C-2, C-3 double bond was also required, but when the A ring is opened, the requirement for the double bond was eliminated. Genistein has been previously reported to stabilize the covalent topo II-DNA cleavage complex and thus function as a topo II poison. All flavonoids were tested for their ability to stabilize the cleavage complex between topo I or topo II and DNA. None of the agents stabilized the topo I-DNA cleavage complex, but prunetin, quercetin, kaempferol, and apigenin stabilized the topo II DNA-complex. Competition experiments have shown that genistein-induced topo II-mediated DNA cleavage can be inhibited by myricetin, suggesting that both types of inhibitors (antagonists and poisons) interact with the same functional domain of their target enzyme. These results are of use for the selection of flavonoids that can inhibit specific topoisomerases at specific stages of the topoisomerization reaction.
|
Inhibition of EGFR
|
None
|
0.2
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Isolation of a novel tyrosine kinase inhibitor, lavendustin A, from Streptomyces griseolavendus.
Year : 1989
Volume : 52
Issue : 6
First Page : 1252
Last Page : 1257
Authors : Onoda T, Iinuma H, Sasaki Y, Hamada M, Isshiki K, Naganawa H, Takeuchi T, Tatsuta K, Umezawa K.
Abstract : A potent tyrosine kinase inhibitor, lavendustin A [1], has been isolated from a butyl acetate extract of Streptomyces griseolavendus culture filtrate. It inhibits epidermal growth factor receptor-associated tyrosine kinase with an IC50 of 4.4 ng/ml, which is about 50 times more inhibitory than erbstatin. It does not inhibit protein kinase A or C. Its structure, determined by spectral data and total synthesis, is novel, having a tertiary amine in the center with substituted benzyl and phenyl groups. Lavendustin A competes with ATP and is noncompetitive with the peptide. Its structure-activity relationship is discussed.
|
Inhibition of beef heart mitochondrial NADH oxidase assessed per mg of protein
|
Bos taurus
|
365.0
nM
|
|
Journal : J. Nat. Prod.
Title : Inhibition of mitochondrial NADH oxidase, succinoxidase, and ATPase by naturally occurring flavonoids.
Year : 1987
Volume : 50
Issue : 3
First Page : 427
Last Page : 433
Authors : Bohmont C, Aaronson LM, Mann K, Pardini RS.
Abstract : A structure-activity investigation of the inhibition of beef heart mitochondrial NADH oxidase and succinoxidase and rat liver mitochondrial ATPase by flavonoids was conducted. NADH oxidase was the most sensitive to inhibition by flavonoids: 13 of the 18 flavonoids tested inhibited NADH oxidase, whereas only 4 and 5 flavonoids inhibited succinoxidase and ATPase, respectively. The flavonoids possessing a catechol or pyrogallol moiety, and a 2,3-double bond and a 3-hydroxyl group were the most inhibitory towards the respiratory chain enzymes. The catechol or pyrogallol moiety did not exert preferential activity towards the oligomycin-sensitive ATPase because morin, which contains a meta-dihydroxy configuration, was the most potent ATPase inhibitor.
|
Inhibition of cow milk xanthine oxidase at 50 ug/mL
|
Bos taurus
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Inhibition of cow's milk xanthine oxidase by flavonoids.
Year : 1988
Volume : 51
Issue : 2
First Page : 345
Last Page : 348
Authors : Hayashi T, Sawa K, Kawasaki M, Arisawa M, Shimizu M, Morita N.
|
Displacement of [3H]estradiol from human recombinant ERalpha
|
Homo sapiens
|
300.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isolation and structure elucidation of an isoflavone and a sesterterpenoic acid from Henriettella fascicularis.
Year : 2002
Volume : 65
Issue : 12
First Page : 1749
Last Page : 1753
Authors : Calderón AI, Terreaux C, Schenk K, Pattison P, Burdette JE, Pezzuto JM, Gupta MP, Hostettmann K.
Abstract : A new isoflavone, 4',5,7-trihydroxy-6,8-dimethylisoflavone (1), and a new sesterterpenoic acid (2), together with five known compounds, lichexanthone (3), (-)-pinoresinol (4), betulinic acid, palmitic acid, and beta-sitosterol, were isolated from a dichloromethane extract of the branches of Henriettella fascicularis. Their structures were established by extensive spectroscopic methods. An attempt to determine the absolute stereochemistry of (2E,6S)-6-[(1R,5Z,3aS,9R,10Z,12aR)-1,2,3,3a,4,7,8,9,12,12a-decahydro-9-hydroxy-3a,6,10-trimethylcyclopentanocycloundecen-1-yl]-2-methylhept-2-enoic acid (2) was performed by single-crystal X-ray analysis, using Cu Kalpha radiation. Compound 1 showed significant competitive binding to estrogen receptor beta and moderate antiestrogenic activity with cultured Ishikawa cells.
|
Inhibition of Saccharomyces cerevisiae fatty acid synthase
|
Saccharomyces cerevisiae
|
50.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies.
Year : 2002
Volume : 65
Issue : 12
First Page : 1909
Last Page : 1914
Authors : Li XC, Joshi AS, ElSohly HN, Khan SI, Jacob MR, Zhang Z, Khan IA, Ferreira D, Walker LA, Broedel SE, Raulli RE, Cihlar RL.
Abstract : Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined.
|
Antifungal activity against Candida albicans ATCC 90028
|
Candida albicans
|
50.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies.
Year : 2002
Volume : 65
Issue : 12
First Page : 1909
Last Page : 1914
Authors : Li XC, Joshi AS, ElSohly HN, Khan SI, Jacob MR, Zhang Z, Khan IA, Ferreira D, Walker LA, Broedel SE, Raulli RE, Cihlar RL.
Abstract : Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined.
|
Antifungal activity against Cryptococcus neoformans ATCC 90113
|
Cryptococcus neoformans
|
50.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies.
Year : 2002
Volume : 65
Issue : 12
First Page : 1909
Last Page : 1914
Authors : Li XC, Joshi AS, ElSohly HN, Khan SI, Jacob MR, Zhang Z, Khan IA, Ferreira D, Walker LA, Broedel SE, Raulli RE, Cihlar RL.
Abstract : Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined.
|
Inhibition of EGFR in human A431 cells
|
Homo sapiens
|
0.1
ug.mL-1
|
|
Inhibition of EGFR in human A431 cells
|
Homo sapiens
|
0.7
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Protein-tyrosine kinase inhibition: mechanism-based discovery of antitumor agents.
Year : 1992
Volume : 55
Issue : 11
First Page : 1529
Last Page : 1560
Authors : Chang CJ, Geahlen RL.
Abstract : Protein-tyrosine kinases (PTKs) have been shown to induce the cascade of altered cell parameters characteristic of transformed cells. This proposition provides an important rationale for the discovery of potential antitumor agents from natural sources on the basis of inhibition of PTK activity. Numerous naturally occurring and synthetic analogues of PTK inhibitors were systematically evaluated in this review based on their structure-activity relationships and potential antitumor efficacy.
|
Inhibition of EGFR
|
None
|
0.7
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Protein-tyrosine kinase inhibition: mechanism-based discovery of antitumor agents.
Year : 1992
Volume : 55
Issue : 11
First Page : 1529
Last Page : 1560
Authors : Chang CJ, Geahlen RL.
Abstract : Protein-tyrosine kinases (PTKs) have been shown to induce the cascade of altered cell parameters characteristic of transformed cells. This proposition provides an important rationale for the discovery of potential antitumor agents from natural sources on the basis of inhibition of PTK activity. Numerous naturally occurring and synthetic analogues of PTK inhibitors were systematically evaluated in this review based on their structure-activity relationships and potential antitumor efficacy.
|
Antifungal activity against MDR knockout Candida albicans DSY1024 after 24 hrs by XTT assay
|
Candida albicans
|
100.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Three new phenolic compounds from a manipulated plant cell culture, Mirabilis jalapa.
Year : 2001
Volume : 64
Issue : 3
First Page : 313
Last Page : 317
Authors : Yang SW, Ubillas R, McAlpine J, Stafford A, Ecker DM, Talbot MK, Rogers B.
Abstract : Bioassay-guided fractionation of an organic extract of the cell mass from a manipulated plant cell culture of Mirabilis jalapa led to the isolation and subsequent identification of three new phenolic compounds, 1, 2, and 3. The isoflavone 1 and dehydrorotenoid 2 were identified as the principal antifungal principles from this plant cell culture with IC(50)'s of 25 and 48 microg/mL, respectively, against the test organism, Candida albicans DSY1024. The rotenoid 3 was inactive at 200 microg/mL in this assay.
|
Antifungal activity against wild type Candida albicans SC5314 after 24 hrs by XTT assay
|
Candida albicans SC5314
|
100.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Three new phenolic compounds from a manipulated plant cell culture, Mirabilis jalapa.
Year : 2001
Volume : 64
Issue : 3
First Page : 313
Last Page : 317
Authors : Yang SW, Ubillas R, McAlpine J, Stafford A, Ecker DM, Talbot MK, Rogers B.
Abstract : Bioassay-guided fractionation of an organic extract of the cell mass from a manipulated plant cell culture of Mirabilis jalapa led to the isolation and subsequent identification of three new phenolic compounds, 1, 2, and 3. The isoflavone 1 and dehydrorotenoid 2 were identified as the principal antifungal principles from this plant cell culture with IC(50)'s of 25 and 48 microg/mL, respectively, against the test organism, Candida albicans DSY1024. The rotenoid 3 was inactive at 200 microg/mL in this assay.
|
Displacement of [3H]estradiol from human recombinant ERbeta
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isolation and structure elucidation of an isoflavone and a sesterterpenoic acid from Henriettella fascicularis.
Year : 2002
Volume : 65
Issue : 12
First Page : 1749
Last Page : 1753
Authors : Calderón AI, Terreaux C, Schenk K, Pattison P, Burdette JE, Pezzuto JM, Gupta MP, Hostettmann K.
Abstract : A new isoflavone, 4',5,7-trihydroxy-6,8-dimethylisoflavone (1), and a new sesterterpenoic acid (2), together with five known compounds, lichexanthone (3), (-)-pinoresinol (4), betulinic acid, palmitic acid, and beta-sitosterol, were isolated from a dichloromethane extract of the branches of Henriettella fascicularis. Their structures were established by extensive spectroscopic methods. An attempt to determine the absolute stereochemistry of (2E,6S)-6-[(1R,5Z,3aS,9R,10Z,12aR)-1,2,3,3a,4,7,8,9,12,12a-decahydro-9-hydroxy-3a,6,10-trimethylcyclopentanocycloundecen-1-yl]-2-methylhept-2-enoic acid (2) was performed by single-crystal X-ray analysis, using Cu Kalpha radiation. Compound 1 showed significant competitive binding to estrogen receptor beta and moderate antiestrogenic activity with cultured Ishikawa cells.
|
Estrogenic activity in human Ishikawa cells assessed as induction of alkaline phosphatase activity after 4 days by para-nitrophenol release assay
|
Homo sapiens
|
510.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isolation and structure elucidation of an isoflavone and a sesterterpenoic acid from Henriettella fascicularis.
Year : 2002
Volume : 65
Issue : 12
First Page : 1749
Last Page : 1753
Authors : Calderón AI, Terreaux C, Schenk K, Pattison P, Burdette JE, Pezzuto JM, Gupta MP, Hostettmann K.
Abstract : A new isoflavone, 4',5,7-trihydroxy-6,8-dimethylisoflavone (1), and a new sesterterpenoic acid (2), together with five known compounds, lichexanthone (3), (-)-pinoresinol (4), betulinic acid, palmitic acid, and beta-sitosterol, were isolated from a dichloromethane extract of the branches of Henriettella fascicularis. Their structures were established by extensive spectroscopic methods. An attempt to determine the absolute stereochemistry of (2E,6S)-6-[(1R,5Z,3aS,9R,10Z,12aR)-1,2,3,3a,4,7,8,9,12,12a-decahydro-9-hydroxy-3a,6,10-trimethylcyclopentanocycloundecen-1-yl]-2-methylhept-2-enoic acid (2) was performed by single-crystal X-ray analysis, using Cu Kalpha radiation. Compound 1 showed significant competitive binding to estrogen receptor beta and moderate antiestrogenic activity with cultured Ishikawa cells.
|
Antiinflammatory activity against FMLP/CB stimulated human neutrophils assessed as inhibition of elastase release at 10 ug/mL relative to control
|
Homo sapiens
|
51.6
%
|
|
Journal : J. Nat. Prod.
Title : Frajunolides E-K, briarane diterpenes from Junceella fragilis.
Year : 2008
Volume : 71
Issue : 9
First Page : 1551
Last Page : 1556
Authors : Liaw CC, Shen YC, Lin YS, Hwang TL, Kuo YH, Khalil AT.
Abstract : Chemical investigation of the gorgonian octocoral Junceella fragilis, collected in Taiwan, resulted in the isolation of seven new briarane-type diterpenes, frajunolides E-K (1-7), in addition to 14 known briaranes, praelolide, junceellin, junceellolides A-E, and K, 11a,20a-epoxy-4-deacetoxyjunceelolide D, umbraculolide A, junceellonoid A, and juncins Y, Z, and ZI, as well as ergosterol peroxide. The structures of 1-7 were determined by analysis of HRESIMS and 2D NMR spectroscopic data. Cytotoxicity and in vitro anti-inflammatory activities of compounds 1-7 were also evaluated.
|
Antiinflammatory activity against FMLP/CB stimulated human neutrophils assessed as inhibition of superoxide anion generation at 10 ug/mL relative to control
|
Homo sapiens
|
65.0
%
|
|
Journal : J. Nat. Prod.
Title : Frajunolides E-K, briarane diterpenes from Junceella fragilis.
Year : 2008
Volume : 71
Issue : 9
First Page : 1551
Last Page : 1556
Authors : Liaw CC, Shen YC, Lin YS, Hwang TL, Kuo YH, Khalil AT.
Abstract : Chemical investigation of the gorgonian octocoral Junceella fragilis, collected in Taiwan, resulted in the isolation of seven new briarane-type diterpenes, frajunolides E-K (1-7), in addition to 14 known briaranes, praelolide, junceellin, junceellolides A-E, and K, 11a,20a-epoxy-4-deacetoxyjunceelolide D, umbraculolide A, junceellonoid A, and juncins Y, Z, and ZI, as well as ergosterol peroxide. The structures of 1-7 were determined by analysis of HRESIMS and 2D NMR spectroscopic data. Cytotoxicity and in vitro anti-inflammatory activities of compounds 1-7 were also evaluated.
|
Antifungal activity against Giardia intestinalis ATCC 30888 after 48 hrs by XTT assay
|
Giardia intestinalis
|
5.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Antigiardial activity of isoflavones from Dalbergia frutescens bark.
Year : 2000
Volume : 63
Issue : 10
First Page : 1414
Last Page : 1416
Authors : Khan IA, Avery MA, Burandt CL, Goins DK, Mikell JR, Nash TE, Azadegan A, Walker LA.
Abstract : Several isoflavones [formononetin (1), castanin (5), odoratin (6), glycitein (7), pseudobaptogenin (8), fujikinetin (9), and cuneatin (10)] were isolated from Dalbergia frutescens, and their antiprotozoal activities were determined against Giardia intestinalis. Among these compounds, formononetin (1) was the most potent antigiardial agent, with an IC(50) value of 30 ng/mL (approximately 0.1 microM), as compared to the value for metronidazole, the current drug of choice, of 100 ng/mL (approximately 0.6 microM). Three isoflavones closely related to formononetin [daidzein (2), biochanin A (3) and genistein (4)] were also evaluated, but they were at least 100 times less active than 1. Formononetin (1) may thus be an interesting lead for development of new antigiardial agents or as a probe for a new mechanistic target.
|
Inhibition of EGFR
|
None
|
0.2
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : A common protein fold topology shared by flavonoid biosynthetic enzymes and therapeutic targets.
Year : 2006
Volume : 69
Issue : 1
First Page : 14
Last Page : 17
Authors : McArdle BM, Campitelli MR, Quinn RJ.
Abstract : The relationship between a natural product's biosynthetic enzyme and its therapeutic target is unknown. The concept of protein fold topologies, as a determining factor in recognition, has been developed through molecular modeling techniques. We have shown that biosynthetic enzymes and the therapeutic targets of three classes of natural products that inhibit protein kinases share a common protein fold topology (PFT) and cavity recognition points despite having different fold type classifications. The clinical agent flavopiridol would have been identified by this new approach.
|
Inhibition of human salivary alpha-amylase
|
Homo sapiens
|
25.1
%
|
|
Journal : J. Med. Chem.
Title : Flavonoids for controlling starch digestion: structural requirements for inhibiting human alpha-amylase.
Year : 2008
Volume : 51
Issue : 12
First Page : 3555
Last Page : 3561
Authors : Lo Piparo E, Scheib H, Frei N, Williamson G, Grigorov M, Chou CJ.
Abstract : In this study we investigated the structural requirements for inhibition of human salivary alpha-amylase by flavonoids. Four flavonols and three flavones, out of the 19 flavonoids tested, exhibited IC50 values less than 100 microM against human salivary alpha-amylase activity. Structure-activity relationships of these inhibitors by computational ligand docking showed that the inhibitory activity of flavonols and flavones depends on (i) hydrogen bonds between the hydroxyl groups of the polyphenol ligands and the catalytic residues of the binding site and (ii) formation of a conjugated pi-system that stabilizes the interaction with the active site. Our findings show that certain naturally occurring flavonoids act as inhibitors of human alpha-amylase, which makes them promising candidates for controlling the digestion of starch and postprandial glycemia.
|
Inhibition of reduced carboxymethylated kappa-casein fibril formation at 50 ug/mL measured every 5 mins after 1000 mins by thioflavin T staining-based binding assay
|
None
|
95.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Carboxymethylated-kappa-casein: a convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation.
Year : 2010
Volume : 18
Issue : 1
First Page : 222
Last Page : 228
Authors : Carver JA, Duggan PJ, Ecroyd H, Liu Y, Meyer AG, Tranberg CE.
Abstract : Reduced and carboxymethylated-kappa-casein (RCM-kappa-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Abeta), which is associated with Alzheimer's disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.
|
Inhibition of beta amyloid (1 to 42) fibril formation at 50 ug/mL by thioflavin T staining-based binding assay
|
None
|
43.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Carboxymethylated-kappa-casein: a convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation.
Year : 2010
Volume : 18
Issue : 1
First Page : 222
Last Page : 228
Authors : Carver JA, Duggan PJ, Ecroyd H, Liu Y, Meyer AG, Tranberg CE.
Abstract : Reduced and carboxymethylated-kappa-casein (RCM-kappa-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Abeta), which is associated with Alzheimer's disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.
|
Inhibition of EGFR at 100 uM by ELISA
|
None
|
80.0
%
|
|
Journal : J. Nat. Prod.
Title : Bioactive diterpene derivatives from the marine sponge Spongionella sp.
Year : 2009
Volume : 72
Issue : 8
First Page : 1471
Last Page : 1476
Authors : Rateb ME, Houssen WE, Schumacher M, Harrison WT, Diederich M, Ebel R, Jaspars M.
Abstract : Three new compounds of the rare classes trisnorditerpenes, bisnorditerpenes, and norditerpenes, gracilins J-L (1, 2, 6), and a new diterpene, 3'-norspongiolactone (8), were isolated from the extract of the marine sponge Spongionella sp. using NMR- and bioassay-guided fractionation, in addition to three known gracilins (3-5) as well as the known diterpenoid tetrahydroaplysulphurin-1 (7). The structures were elucidated using NMR spectroscopic techniques and mass spectrometric analysis. The structure of gracilin H (3) was confirmed by single-crystal X-ray analysis. All compounds were tested for their cytotoxicity and for their potential to inhibit EGF-R tyrosine kinase.
|
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 0.3 uM after 7 hrs
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
Year : 2009
Volume : 52
Issue : 23
First Page : 7488
Last Page : 7502
Authors : Bellavance E, Luu-The V, Poirier D.
Abstract : 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
|
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 3 uM after 7 hrs
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
Year : 2009
Volume : 52
Issue : 23
First Page : 7488
Last Page : 7502
Authors : Bellavance E, Luu-The V, Poirier D.
Abstract : 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/cytochalasin B-induced elastase release at 10 ug/ml after 5 mins
|
Homo sapiens
|
52.0
%
|
|
Journal : J. Nat. Prod.
Title : Asterolaurins A-F, xenicane diterpenoids from the Taiwanese soft coral Asterospicularia laurae.
Year : 2009
Volume : 72
Issue : 11
First Page : 1911
Last Page : 1916
Authors : Lin YC, Abd El-Razek MH, Hwang TL, Chiang MY, Kuo YH, Dai CF, Shen YC.
Abstract : Six new xenicane-type diterpenoids, designated as asterolaurins A-F (1-6), have been isolated from the organic extract of the soft coral Asterospicularia laurae, collected in southern Taiwan. Compounds 1-4 possess a xenicin skeleton with a 2-oxabicyclo[7.4.0]tridecane ring system, while 5 and 6 are xeniolide A-type compounds. The structures of the new secondary metabolites, including their configurations, were established on the basis of an extensive spectroscopic analysis, including 1D and 2D NMR (1H-1H COSY, HMQC, HMBC, and NOESY), and by comparison of their NMR data with those of the related compounds. The structure of asterolaurin A (1) was confirmed by X-ray diffraction analysis, and its absolute configuration was determined using the modified Mosher's method. Asterolaurin A (1) exhibited moderate cytotoxicity against HepG2 cells with an IC50 of 8.9 microM, while asterolaurin D (4) showed potent inhibition of elastase release and superoxide anion generation in vitro.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/cytochalasin B-induced superoxide anion generation at 10 ug/ml after 5 mins by spectrophotometry
|
Homo sapiens
|
65.0
%
|
|
Journal : J. Nat. Prod.
Title : Asterolaurins A-F, xenicane diterpenoids from the Taiwanese soft coral Asterospicularia laurae.
Year : 2009
Volume : 72
Issue : 11
First Page : 1911
Last Page : 1916
Authors : Lin YC, Abd El-Razek MH, Hwang TL, Chiang MY, Kuo YH, Dai CF, Shen YC.
Abstract : Six new xenicane-type diterpenoids, designated as asterolaurins A-F (1-6), have been isolated from the organic extract of the soft coral Asterospicularia laurae, collected in southern Taiwan. Compounds 1-4 possess a xenicin skeleton with a 2-oxabicyclo[7.4.0]tridecane ring system, while 5 and 6 are xeniolide A-type compounds. The structures of the new secondary metabolites, including their configurations, were established on the basis of an extensive spectroscopic analysis, including 1D and 2D NMR (1H-1H COSY, HMQC, HMBC, and NOESY), and by comparison of their NMR data with those of the related compounds. The structure of asterolaurin A (1) was confirmed by X-ray diffraction analysis, and its absolute configuration was determined using the modified Mosher's method. Asterolaurin A (1) exhibited moderate cytotoxicity against HepG2 cells with an IC50 of 8.9 microM, while asterolaurin D (4) showed potent inhibition of elastase release and superoxide anion generation in vitro.
|
Inhibition of Influenza A PR/8/34 H1N1 virus neuraminidase activity by MUN-ANA substrate based fluorimetric assay
|
Influenza A virus (A/Puerto Rico/8/1934(H1N1))
|
20.84
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : QSAR study of flavonoids and biflavonoids as influenza H1N1 virus neuraminidase inhibitors.
Year : 2010
Volume : 45
Issue : 5
First Page : 1724
Last Page : 1730
Authors : Mercader AG, Pomilio AB.
Abstract : We performed a predictive analysis based on Quantitative Structure-Activity Relationships (QSAR) of a very important property of flavonoids which is the inhibition (IC50) of influenza H1N1 virus neuraminidase. The best linear model constructed from 20 molecular structures incorporated four molecular descriptors, selected from more than a thousand geometrical, topological, quantum-mechanical and electronic types of descriptors. The obtained model suggests that the activity depends on the electric charges, masses and polarizabilities of the atoms present in the molecule as well as its conformation. The model showed good predictive ability established by the theoretical and external test set validations.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of FMLP/CB-induced elastase release at 10 ug/mL
|
Homo sapiens
|
51.6
%
|
|
Journal : J. Nat. Prod.
Title : Nortriterpene lactones from the fruits of Schisandra arisanensis.
Year : 2010
Volume : 73
Issue : 7
First Page : 1228
Last Page : 1233
Authors : Cheng YB, Liao TC, Lo YW, Chen YC, Kuo YC, Chen SY, Chien CT, Hwang TL, Shen YC.
Abstract : Fractionation of an acetone extract from the fruits of Schisandra arisanensis afforded five new nortriterpene lactones, compounds 1-5, together with four known compounds, schindilactones D and E (6 and 7) and preschisanartanins A and B (8 and 9). Compound 1, a wuweiziartane-type nortriterpenoid, possesses a new type of fused ring system with a gamma-lactone ring between C-15 and C-17. Compounds 2, 6, and 7 may be categorized as schisanartane-type nortriterpenoids and compounds 3-5, 8, and 9 as preschisanartane-type nortriterpenoids. The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopic data interpretation. The structure and relative configuration of 3 were supported by single-crystal X-ray diffraction analysis. The antiviral activity against HSV-1 and inhibitory effects on superoxide anion generation and elastase release by human neutrophils in response to FMLP/CB of compounds 1-9 were evaluated.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum Dd2
|
Plasmodium falciparum Dd2
|
4.1
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Antimalarials from nature.
Year : 2009
Volume : 17
Issue : 9
First Page : 3229
Last Page : 3256
Authors : Kaur K, Jain M, Kaur T, Jain R.
Abstract : Malaria is a major public health problem mainly due to the development of resistance by the most lethal causative parasitic species, Plasmodium falciparum to the mainstay drugs like chloroquine. New drugs with unique structures and mechanism of action are urgently required to treat sensitive and drug-resistant strains of malaria. Historically, compounds containing novel structure from natural origin represent a major source for the discovery and development of new drugs for several diseases. This review presents recent advances in antimalarial drug discovery from natural sources, including plant extracts, and compounds isolated from plants, bacteria, fungi and marine organisms. These compounds offer new and novel scaffolds for development as antimalarials. The literature from 1998 to October 2008 is reviewed. The review present literature compilation from plant and marine extracts, alkaloids (naphthylisoquinolines, bisbenzylisoquinolines, protoberberines and aporphines, indoles, manzamines, and miscellaneous alkaloids) terpenes (sesquiterpenes, triterpenes, diterpenes, and miscellaneous terpenes) quassinoids, flavonoids, limonoids, chalcones, peptides, xanthones, quinones and coumarines, and miscellaneous antimalarials from nature. The review also provides an outlook to recent semisynthetic approaches to antimalarial drugs discovered from natural sources.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum PoW
|
Plasmodium falciparum
|
2.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Antimalarials from nature.
Year : 2009
Volume : 17
Issue : 9
First Page : 3229
Last Page : 3256
Authors : Kaur K, Jain M, Kaur T, Jain R.
Abstract : Malaria is a major public health problem mainly due to the development of resistance by the most lethal causative parasitic species, Plasmodium falciparum to the mainstay drugs like chloroquine. New drugs with unique structures and mechanism of action are urgently required to treat sensitive and drug-resistant strains of malaria. Historically, compounds containing novel structure from natural origin represent a major source for the discovery and development of new drugs for several diseases. This review presents recent advances in antimalarial drug discovery from natural sources, including plant extracts, and compounds isolated from plants, bacteria, fungi and marine organisms. These compounds offer new and novel scaffolds for development as antimalarials. The literature from 1998 to October 2008 is reviewed. The review present literature compilation from plant and marine extracts, alkaloids (naphthylisoquinolines, bisbenzylisoquinolines, protoberberines and aporphines, indoles, manzamines, and miscellaneous alkaloids) terpenes (sesquiterpenes, triterpenes, diterpenes, and miscellaneous terpenes) quassinoids, flavonoids, limonoids, chalcones, peptides, xanthones, quinones and coumarines, and miscellaneous antimalarials from nature. The review also provides an outlook to recent semisynthetic approaches to antimalarial drugs discovered from natural sources.
|
Inhibition of human aldehyde oxidase
|
Homo sapiens
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Aldehyde oxidase: an enzyme of emerging importance in drug discovery.
Year : 2010
Volume : 53
Issue : 24
First Page : 8441
Last Page : 8460
Authors : Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/CB-induced superoxide anion generation after 5 mins
|
Homo sapiens
|
0.54
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel alkaloid, aristopyridinone A and anti-inflammatory phenanthrenes isolated from Aristolochia manshuriensis.
Year : 2011
Volume : 21
Issue : 6
First Page : 1792
Last Page : 1794
Authors : Chung YM, Chang FR, Tseng TF, Hwang TL, Chen LC, Wu SF, Lee CL, Lin ZY, Chuang LY, Su JH, Wu YC.
Abstract : A novel alkaloid, aristopyridinone A (1) and a new phenanthrene, aristolamide II (2), were isolated from Aristolochia manshuriensis (Guanmutong) together with eight known phenanthrenes (3-10). All structures were elucidated by spectroscopic methods. Compound 2 showed a selective inhibitory effect on elastase release by human neutrophils in response to fMLP with an IC(50) value of 4.11 μg/mL. Compound 7 exhibited significant inhibitory effects on superoxide anion generation and elastase release with IC(50) values of 0.12 and 0.20 μg/mL, respectively.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/CB-induced elastase release after 5 mins
|
Homo sapiens
|
6.99
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel alkaloid, aristopyridinone A and anti-inflammatory phenanthrenes isolated from Aristolochia manshuriensis.
Year : 2011
Volume : 21
Issue : 6
First Page : 1792
Last Page : 1794
Authors : Chung YM, Chang FR, Tseng TF, Hwang TL, Chen LC, Wu SF, Lee CL, Lin ZY, Chuang LY, Su JH, Wu YC.
Abstract : A novel alkaloid, aristopyridinone A (1) and a new phenanthrene, aristolamide II (2), were isolated from Aristolochia manshuriensis (Guanmutong) together with eight known phenanthrenes (3-10). All structures were elucidated by spectroscopic methods. Compound 2 showed a selective inhibitory effect on elastase release by human neutrophils in response to fMLP with an IC(50) value of 4.11 μg/mL. Compound 7 exhibited significant inhibitory effects on superoxide anion generation and elastase release with IC(50) values of 0.12 and 0.20 μg/mL, respectively.
|
Negative chronotropic activity against potassium-induced contraction in guinea pig right atrium assessed as decrease atrial rate at 10'-4 M relative to control
|
Cavia porcellus
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.
Year : 2011
Volume : 54
Issue : 11
First Page : 3885
Last Page : 3894
Authors : Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ.
Abstract : The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
|
Negative ionotropic activity against potassium-induced contraction in guinea pig left atrium assessed as decrease atrial rate at 5 X 10'-6 M relative to control
|
Cavia porcellus
|
71.0
%
|
|
Journal : J. Med. Chem.
Title : Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.
Year : 2011
Volume : 54
Issue : 11
First Page : 3885
Last Page : 3894
Authors : Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ.
Abstract : The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
|
Negative ionotropic activity against potassium-induced contraction in guinea pig left atrium assessed as decrease atrial rate
|
Cavia porcellus
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.
Year : 2011
Volume : 54
Issue : 11
First Page : 3885
Last Page : 3894
Authors : Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ.
Abstract : The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
|
Vasorelaxant activity in potassium depolarized guinea pig aortic strip assessed as inhibition of calcium-induced contraction at 5 X 10'-5 M
|
Cavia porcellus
|
22.0
%
|
|
Journal : J. Med. Chem.
Title : Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.
Year : 2011
Volume : 54
Issue : 11
First Page : 3885
Last Page : 3894
Authors : Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ.
Abstract : The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
|
Negative ionotropic activity in potassium depolarized guinea pig longitudinal smooth muscle assessed as inhibition of calcium-induced contraction at 5 X 10'-5 M
|
Cavia porcellus
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.
Year : 2011
Volume : 54
Issue : 11
First Page : 3885
Last Page : 3894
Authors : Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ.
Abstract : The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
|
Bronchodilatory activity in guinea pig trachea assessed as inhibition of carbachol-induced contraction at 10'-5 M
|
Cavia porcellus
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.
Year : 2011
Volume : 54
Issue : 11
First Page : 3885
Last Page : 3894
Authors : Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ.
Abstract : The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
|
DRUGMATRIX: Estrogen ERalpha radioligand binding (ligand: [3H] Estradiol)
|
None
|
135.0
nM
|
|
DRUGMATRIX: Estrogen ERalpha radioligand binding (ligand: [3H] Estradiol)
|
None
|
39.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Estrogen ERbeta radioligand binding (ligand: [3H] Estradiol)
|
None
|
2.88
nM
|
|
DRUGMATRIX: Estrogen ERbeta radioligand binding (ligand: [3H] Estradiol)
|
None
|
0.594
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
7.3
%
|
|
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
|
10.47
%
|
|
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 human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
84.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-5.0
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
67.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of FMLP-induced superoxide anion production treated 5 mins before FMLP addition measured after 10 mins
|
Homo sapiens
|
690.0
nM
|
|
Journal : J. Nat. Prod.
Title : Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, induces the production of anti-inflammatory cyclodepsipeptides from Beauveria felina.
Year : 2013
Volume : 76
Issue : 7
First Page : 1260
Last Page : 1266
Authors : Chung YM, El-Shazly M, Chuang DW, Hwang TL, Asai T, Oshima Y, Ashour ML, Wu YC, Chang FR.
Abstract : The addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid to a culture of the filamentous fungus Beauveria felina significantly changed its secondary metabolite profile and led to the isolation of eight compounds, including three new cyclodepsipeptides, desmethylisaridin E (1), desmethylisaridin C2 (2), and isaridin F (3), along with five known cyclodepsipeptide compounds. Isaridin F (3) possesses a cyclodepsipeptide ring with N-methylbutyric acid, which is rare in natural peptides. Absolute configurations of the new cyclodepsipeptides were achieved by Marfey's method. The anti-inflammatory activity of the isolated compounds was investigated through evaluating their effect on superoxide anion production and elastase release by FMLP-induced human neutrophils. Among the tested compounds, desmethylisaridin E (1) inhibited superoxide anion production and desmethylisaridin C2 (2) inhibited elastase release, with IC50 values of 10.00 ± 0.80 and 10.01 ± 0.46 μM, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
95.56
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
39.06
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of rat serum BuChE using butyrylthiocholine iodide as substrate at 50 uM after 15 mins by Ellman's method
|
Rattus norvegicus
|
5.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease.
Year : 2014
Volume : 76
First Page : 314
Last Page : 331
Authors : Qiang X, Sang Z, Yuan W, Li Y, Liu Q, Bai P, Shi Y, Ang W, Tan Z, Deng Y.
Abstract : A series of genistein derivatives with carbon spacer-linked alkylbenzylamines were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good acetylcholinesterase (AChE) inhibitory activity, with moderate-to-good anti-oxidative activity. Specifically, compounds 10b, 19d and 25d exhibited significant inhibition of β-amyloid (Aβ) aggregation and exhibited metal chelating properties. In particular, 25d inhibited: self-induced Aβ₁₋₄₂ aggregation, Cu(2+)-induced Aβ₁₋₄₂ aggregation, and human AChE-induced Aβ₁₋₄₀ aggregation by 35%, 77.8%, and 36.2%, respectively. Moreover, both kinetic analysis of AChE inhibition and the molecular modeling study suggested that 25d binds simultaneously to catalytic active site and peripheral anionic site of AChE. More importantly, compound 25d disassembled the well-structured Aβ fibrils generated by Cu(2+)-induced Aβ aggregation by 72.1%. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. These results suggest that 25d may be a promising multifunctional agent for AD treatment.
|
Inhibition of human erythrocytes AchE using acetylthiocholine iodide as substrate at 50 uM after 15 mins by Ellman's method
|
Homo sapiens
|
5.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease.
Year : 2014
Volume : 76
First Page : 314
Last Page : 331
Authors : Qiang X, Sang Z, Yuan W, Li Y, Liu Q, Bai P, Shi Y, Ang W, Tan Z, Deng Y.
Abstract : A series of genistein derivatives with carbon spacer-linked alkylbenzylamines were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good acetylcholinesterase (AChE) inhibitory activity, with moderate-to-good anti-oxidative activity. Specifically, compounds 10b, 19d and 25d exhibited significant inhibition of β-amyloid (Aβ) aggregation and exhibited metal chelating properties. In particular, 25d inhibited: self-induced Aβ₁₋₄₂ aggregation, Cu(2+)-induced Aβ₁₋₄₂ aggregation, and human AChE-induced Aβ₁₋₄₀ aggregation by 35%, 77.8%, and 36.2%, respectively. Moreover, both kinetic analysis of AChE inhibition and the molecular modeling study suggested that 25d binds simultaneously to catalytic active site and peripheral anionic site of AChE. More importantly, compound 25d disassembled the well-structured Aβ fibrils generated by Cu(2+)-induced Aβ aggregation by 72.1%. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. These results suggest that 25d may be a promising multifunctional agent for AD treatment.
|
Inhibition of electric eel AchE using acetylthiocholine iodide as substrate at 50 uM after 15 mins by Ellman's method
|
Electrophorus electricus
|
5.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease.
Year : 2014
Volume : 76
First Page : 314
Last Page : 331
Authors : Qiang X, Sang Z, Yuan W, Li Y, Liu Q, Bai P, Shi Y, Ang W, Tan Z, Deng Y.
Abstract : A series of genistein derivatives with carbon spacer-linked alkylbenzylamines were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good acetylcholinesterase (AChE) inhibitory activity, with moderate-to-good anti-oxidative activity. Specifically, compounds 10b, 19d and 25d exhibited significant inhibition of β-amyloid (Aβ) aggregation and exhibited metal chelating properties. In particular, 25d inhibited: self-induced Aβ₁₋₄₂ aggregation, Cu(2+)-induced Aβ₁₋₄₂ aggregation, and human AChE-induced Aβ₁₋₄₀ aggregation by 35%, 77.8%, and 36.2%, respectively. Moreover, both kinetic analysis of AChE inhibition and the molecular modeling study suggested that 25d binds simultaneously to catalytic active site and peripheral anionic site of AChE. More importantly, compound 25d disassembled the well-structured Aβ fibrils generated by Cu(2+)-induced Aβ aggregation by 72.1%. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. These results suggest that 25d may be a promising multifunctional agent for AD treatment.
|
Inhibition of rat cortex homogenate AchE using acetylthiocholine iodide as substrate at 50 uM after 15 mins by Ellman's method
|
Rattus norvegicus
|
5.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease.
Year : 2014
Volume : 76
First Page : 314
Last Page : 331
Authors : Qiang X, Sang Z, Yuan W, Li Y, Liu Q, Bai P, Shi Y, Ang W, Tan Z, Deng Y.
Abstract : A series of genistein derivatives with carbon spacer-linked alkylbenzylamines were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good acetylcholinesterase (AChE) inhibitory activity, with moderate-to-good anti-oxidative activity. Specifically, compounds 10b, 19d and 25d exhibited significant inhibition of β-amyloid (Aβ) aggregation and exhibited metal chelating properties. In particular, 25d inhibited: self-induced Aβ₁₋₄₂ aggregation, Cu(2+)-induced Aβ₁₋₄₂ aggregation, and human AChE-induced Aβ₁₋₄₀ aggregation by 35%, 77.8%, and 36.2%, respectively. Moreover, both kinetic analysis of AChE inhibition and the molecular modeling study suggested that 25d binds simultaneously to catalytic active site and peripheral anionic site of AChE. More importantly, compound 25d disassembled the well-structured Aβ fibrils generated by Cu(2+)-induced Aβ aggregation by 72.1%. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. These results suggest that 25d may be a promising multifunctional agent for AD treatment.
|
Agonist activity at human ER-beta transfected in HEK293 cells after 48 hrs by luciferase reporter gene assay
|
Homo sapiens
|
19.95
nM
|
|
Journal : MedChemComm
Title : The A-CD analogue of 16,17-estriol is a potent and highly selective estrogen receptor agonist
Year : 2013
Volume : 4
Issue : 11
First Page : 1439
Last Page : 1442
Authors : Sauvee C, Schafer A, Sunden H, Ma J, Gustavsson A, Burstein ES, Olsson R
|
Agonist activity at human ER-alpha transfected in HEK293 cells after 48 hrs by luciferase reporter gene assay
|
Homo sapiens
|
501.19
nM
|
|
Journal : MedChemComm
Title : The A-CD analogue of 16,17-estriol is a potent and highly selective estrogen receptor agonist
Year : 2013
Volume : 4
Issue : 11
First Page : 1439
Last Page : 1442
Authors : Sauvee C, Schafer A, Sunden H, Ma J, Gustavsson A, Burstein ES, Olsson R
|
Antiviral activity against HIV-1 3B infected in human C8166 cells assessed as inhibition of virus-induced cytopathogenicity by measuring syncytial cell number after 3 days by inverted microscopic analysis
|
Human immunodeficiency virus 1
|
13.9
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75.
Year : 2014
Volume : 22
Issue : 12
First Page : 3146
Last Page : 3158
Authors : Li BW, Zhang FH, Serrao E, Chen H, Sanchez TW, Yang LM, Neamati N, Zheng YT, Wang H, Long YQ.
Abstract : HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their β-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3'/4'-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC50=0.826 μg/mL) and high therapeutic index (TI>242). More significantly, these hydroxyflavones block the IN-LEDGF/p75 interaction with low- to sub-micromolar IC50 values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein-protein interaction domains.
|
Inhibition of porcine pancreatic lipase at 100 ug/ml pre-incubated for 15 mins before p-nitrophenylbutyrate substrate addition by microplate reader based method
|
Sus scrofa
|
3.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzylated and prenylated flavonoids from the root barks of Cudrania tricuspidata with pancreatic lipase inhibitory activity.
Year : 2015
Volume : 25
Issue : 17
First Page : 3455
Last Page : 3457
Authors : Jo YH, Kim SB, Liu Q, Lee JW, Hwang BY, Lee MK.
Abstract : A new benzylated and prenylated flavonone, cudracuspiflavanone A (17) were isolated from the roots of Cudrania tricuspidata (Moraceae), together with two chromones (1-2) and fourteen flavonoids (3-16). The structures of isolated compounds were determined on the basis of spectroscopic analysis. The absolute configuration was also defined by CD analysis. Among the isolated compounds, compounds 14 and 15 inhibited pancreatic lipase activity with an IC50 value of 9.0 and 6.5 μM, respectively.
|
Binding Assay: The binding affinity and selectivity of candidate molecules yielded from database screening were determined by a fluorescent polarization competitive binding assay using purified baculovirus-expressed human ER beta or ER alpha and a fluorescent estrogen ligand EL Red (PanVera Corp.).
|
Homo sapiens
|
98.7
nM
|
|
Title : Phytoestrogenic formulations for alleviation or prevention of neurodegenerative diseases
Year : 2013
|
Antiinflammatory activity in mouse RAW264.7 cells assessed as inhibition of LPS-induced NO production at 10 uM after 24 hrs by Griess reagent based assay relative to control
|
Mus musculus
|
13.0
%
|
|
Journal : Bioorg Med Chem
Title : Screening for bioactive natural products from a 67-compound library of Glycyrrhiza inflata.
Year : 2017
Volume : 25
Issue : 14
First Page : 3706
Last Page : 3713
Authors : Lin Y, Kuang Y, Li K, Wang S, Song W, Qiao X, Sabir G, Ye M.
Abstract : Licorice shows a variety of pharmacological activities. This work aims to discover bioactive natural products from one botanical source of licorice, Glycyrrhiza inflata. A total of 67 free phenolics were isolated to form a compound library. Based on the bioactivities of licorice, these compounds were screened using cell- or enzyme-based bioassay methods. A total of 11 compounds exhibited potent cytotoxic activities against three human cancer cell lines (HepG2, SW480 and MCF7), while showed little toxicity on human normal cell lines LO2 and HEK293T. A number of chalcones showed remarkable anti-inflammatory activities. Among them, 2 (licochalcone B, IC50 8.78μM), 10 (licoagrochalcone C, IC50 9.35μM) and 13 (licochalcone E, IC50 9.09μM) exhibited the most potent inhibitory activities on LPS-induced NO production, whereas 1, 8, 10, 12 and 13 (IC50 13.9, 7.27, 2.44, 6.67 and 3.83μM) showed potent inhibitory activities on NF-κB transcription. Nine prenylated phenolics were found to be PTP1B inhibitors. Particularly, licoagrochalcone A (4), kanzonol C (7), 2'-hydroxyisolupalbigenin (35), gancaonin Q (45), glisoflavanone (50) and glabrol (53) showed IC50 values of 0.31-0.97μM. Compounds 24 (semilicoisoflavone B, IC50 0.25μM), 26 (allolicoisoflavone B, IC50 0.80μM) and 64 (glabridin, IC50 0.10μM) showed noticeable tyrosinase inhibitory activities. Most of the above bioactive compounds were reported for the first time.
|
Inhibition of LPS-induced NF-kappaB transcription (unknown origin) expressed in human SW480 cells at 10 uM by luciferase reporter gene assay
|
Homo sapiens
|
14.0
%
|
|
Journal : Bioorg Med Chem
Title : Screening for bioactive natural products from a 67-compound library of Glycyrrhiza inflata.
Year : 2017
Volume : 25
Issue : 14
First Page : 3706
Last Page : 3713
Authors : Lin Y, Kuang Y, Li K, Wang S, Song W, Qiao X, Sabir G, Ye M.
Abstract : Licorice shows a variety of pharmacological activities. This work aims to discover bioactive natural products from one botanical source of licorice, Glycyrrhiza inflata. A total of 67 free phenolics were isolated to form a compound library. Based on the bioactivities of licorice, these compounds were screened using cell- or enzyme-based bioassay methods. A total of 11 compounds exhibited potent cytotoxic activities against three human cancer cell lines (HepG2, SW480 and MCF7), while showed little toxicity on human normal cell lines LO2 and HEK293T. A number of chalcones showed remarkable anti-inflammatory activities. Among them, 2 (licochalcone B, IC50 8.78μM), 10 (licoagrochalcone C, IC50 9.35μM) and 13 (licochalcone E, IC50 9.09μM) exhibited the most potent inhibitory activities on LPS-induced NO production, whereas 1, 8, 10, 12 and 13 (IC50 13.9, 7.27, 2.44, 6.67 and 3.83μM) showed potent inhibitory activities on NF-κB transcription. Nine prenylated phenolics were found to be PTP1B inhibitors. Particularly, licoagrochalcone A (4), kanzonol C (7), 2'-hydroxyisolupalbigenin (35), gancaonin Q (45), glisoflavanone (50) and glabrol (53) showed IC50 values of 0.31-0.97μM. Compounds 24 (semilicoisoflavone B, IC50 0.25μM), 26 (allolicoisoflavone B, IC50 0.80μM) and 64 (glabridin, IC50 0.10μM) showed noticeable tyrosinase inhibitory activities. Most of the above bioactive compounds were reported for the first time.
|
Inhibition of recombinant human PTP1B using p-nitrophenyl phosphate as substrate at 10 uM after 30 mins relative to control
|
Homo sapiens
|
29.0
%
|
|
Journal : Bioorg Med Chem
Title : Screening for bioactive natural products from a 67-compound library of Glycyrrhiza inflata.
Year : 2017
Volume : 25
Issue : 14
First Page : 3706
Last Page : 3713
Authors : Lin Y, Kuang Y, Li K, Wang S, Song W, Qiao X, Sabir G, Ye M.
Abstract : Licorice shows a variety of pharmacological activities. This work aims to discover bioactive natural products from one botanical source of licorice, Glycyrrhiza inflata. A total of 67 free phenolics were isolated to form a compound library. Based on the bioactivities of licorice, these compounds were screened using cell- or enzyme-based bioassay methods. A total of 11 compounds exhibited potent cytotoxic activities against three human cancer cell lines (HepG2, SW480 and MCF7), while showed little toxicity on human normal cell lines LO2 and HEK293T. A number of chalcones showed remarkable anti-inflammatory activities. Among them, 2 (licochalcone B, IC50 8.78μM), 10 (licoagrochalcone C, IC50 9.35μM) and 13 (licochalcone E, IC50 9.09μM) exhibited the most potent inhibitory activities on LPS-induced NO production, whereas 1, 8, 10, 12 and 13 (IC50 13.9, 7.27, 2.44, 6.67 and 3.83μM) showed potent inhibitory activities on NF-κB transcription. Nine prenylated phenolics were found to be PTP1B inhibitors. Particularly, licoagrochalcone A (4), kanzonol C (7), 2'-hydroxyisolupalbigenin (35), gancaonin Q (45), glisoflavanone (50) and glabrol (53) showed IC50 values of 0.31-0.97μM. Compounds 24 (semilicoisoflavone B, IC50 0.25μM), 26 (allolicoisoflavone B, IC50 0.80μM) and 64 (glabridin, IC50 0.10μM) showed noticeable tyrosinase inhibitory activities. Most of the above bioactive compounds were reported for the first time.
|
Inhibition of mushroom tyrosinase at 10 uM using L-tyrosine as substrate incubated for 15 mins followed by substrate addition relative to control
|
Agaricus bisporus
|
2.0
%
|
|
Journal : Bioorg Med Chem
Title : Screening for bioactive natural products from a 67-compound library of Glycyrrhiza inflata.
Year : 2017
Volume : 25
Issue : 14
First Page : 3706
Last Page : 3713
Authors : Lin Y, Kuang Y, Li K, Wang S, Song W, Qiao X, Sabir G, Ye M.
Abstract : Licorice shows a variety of pharmacological activities. This work aims to discover bioactive natural products from one botanical source of licorice, Glycyrrhiza inflata. A total of 67 free phenolics were isolated to form a compound library. Based on the bioactivities of licorice, these compounds were screened using cell- or enzyme-based bioassay methods. A total of 11 compounds exhibited potent cytotoxic activities against three human cancer cell lines (HepG2, SW480 and MCF7), while showed little toxicity on human normal cell lines LO2 and HEK293T. A number of chalcones showed remarkable anti-inflammatory activities. Among them, 2 (licochalcone B, IC50 8.78μM), 10 (licoagrochalcone C, IC50 9.35μM) and 13 (licochalcone E, IC50 9.09μM) exhibited the most potent inhibitory activities on LPS-induced NO production, whereas 1, 8, 10, 12 and 13 (IC50 13.9, 7.27, 2.44, 6.67 and 3.83μM) showed potent inhibitory activities on NF-κB transcription. Nine prenylated phenolics were found to be PTP1B inhibitors. Particularly, licoagrochalcone A (4), kanzonol C (7), 2'-hydroxyisolupalbigenin (35), gancaonin Q (45), glisoflavanone (50) and glabrol (53) showed IC50 values of 0.31-0.97μM. Compounds 24 (semilicoisoflavone B, IC50 0.25μM), 26 (allolicoisoflavone B, IC50 0.80μM) and 64 (glabridin, IC50 0.10μM) showed noticeable tyrosinase inhibitory activities. Most of the above bioactive compounds were reported for the first time.
|
Inhibition of DPP4 (unknown origin) using Gly-Pro-AMC as substrate preincubated for 4 secs followed by substrate addition and measured after 30 mins by luminescence assay
|
Homo sapiens
|
480.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent progress of the development of dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.
Year : 2018
Volume : 151
First Page : 145
Last Page : 157
Authors : Li N, Wang LJ, Jiang B, Li XQ, Guo CL, Guo SJ, Shi DY.
Abstract : Diabetes is a fast growing chronic metabolic disorder around the world. Dipeptidyl peptidase-4 (DPP-4) is a new promising target during type 2 diabetes glycemic control. Thus, a number of potent DPP-4 inhibitors were developed and play a rapidly evolving role in the management of type 2 diabetes in recent years. This article reviews the development of synthetic and natural DPP-4 inhibitors from 2012 to 2017 and provides their physico-chemical properties, biological activities against DPP-4 and selectivity over dipeptidyl peptidase-8/9. Moreover, the glucose-lowering mechanisms and the active site of DPP-4 are also discussed. We also discuss strategies and structure-activity relationships for identifying potent DPP-4 inhibitors, which will provide useful information for developing potent DPP-4 drugs as type 2 diabtes treatments.
|
Estrogenic activity at ERalpha in human Ishikawa cells assessed as induction of alkaline phosphatase activity using p-nitrophenol as substrate treated for 96 hrs followed by substrate addition by spectrophotometric method
|
Homo sapiens
|
240.0
nM
|
|
Journal : J Nat Prod
Title : Estrogen Receptor (ER) Subtype Selectivity Identifies 8-Prenylapigenin as an ERβ Agonist from Glycyrrhiza inflata and Highlights the Importance of Chemical and Biological Authentication.
Year : 2018
Volume : 81
Issue : 4
First Page : 966
Last Page : 975
Authors : Hajirahimkhan A, Mbachu O, Simmler C, Ellis SG, Dong H, Nikolic D, Lankin DC, van Breemen RB, Chen SN, Pauli GF, Dietz BM, Bolton JL.
Abstract : Postmenopausal women are increasingly using botanicals for menopausal symptom relief due to the increased breast cancer risk associated with traditional estrogen therapy. The deleterious effects of estrogens are associated with estrogen receptor (ER)α-dependent proliferation, while ERβ activation could enhance safety by opposing ERα effects. Three medicinal licorice species, Glycyrrhiza glabra ( G. glabra), G. uralensis, and G. inflata, were studied for their differential estrogenic efficacy. The data showed higher estrogenic potency for G. inflata in an alkaline phosphatase induction assay in Ishikawa cells (ERα) and an estrogen responsive element (ERE)-luciferase assay in MDA-MB-231/β41 breast cancer cells (ERβ). Bioassay-guided fractionation of G. inflata led to the isolation of 8-prenylapigenin (3). Surprisingly, a commercial batch of 3 was devoid of estrogenic activity. Quality control by MS and qNMR revealed an incorrect compound, 4'- O-methylbroussochalcone B (10), illustrating the importance of both structural and purity verification prior to any biological investigations. Authentic and pure 3 displayed 14-fold preferential ERβ agonist activity. Quantitative analyses revealed that 3 was 33 times more concentrated in G. inflata compared to the other medicinal licorice extracts. These data suggest that standardization of G. inflata to 3 might enhance the safety and efficacy of G. inflata supplements used for postmenopausal women's health.
|
Estrogenic activity at ERbeta (unknown origin) expressed in human MDA-MB-231/beta41 cells after 18 hrs by renilla luciferase reporter gene assay
|
Homo sapiens
|
2.4
nM
|
|
Journal : J Nat Prod
Title : Estrogen Receptor (ER) Subtype Selectivity Identifies 8-Prenylapigenin as an ERβ Agonist from Glycyrrhiza inflata and Highlights the Importance of Chemical and Biological Authentication.
Year : 2018
Volume : 81
Issue : 4
First Page : 966
Last Page : 975
Authors : Hajirahimkhan A, Mbachu O, Simmler C, Ellis SG, Dong H, Nikolic D, Lankin DC, van Breemen RB, Chen SN, Pauli GF, Dietz BM, Bolton JL.
Abstract : Postmenopausal women are increasingly using botanicals for menopausal symptom relief due to the increased breast cancer risk associated with traditional estrogen therapy. The deleterious effects of estrogens are associated with estrogen receptor (ER)α-dependent proliferation, while ERβ activation could enhance safety by opposing ERα effects. Three medicinal licorice species, Glycyrrhiza glabra ( G. glabra), G. uralensis, and G. inflata, were studied for their differential estrogenic efficacy. The data showed higher estrogenic potency for G. inflata in an alkaline phosphatase induction assay in Ishikawa cells (ERα) and an estrogen responsive element (ERE)-luciferase assay in MDA-MB-231/β41 breast cancer cells (ERβ). Bioassay-guided fractionation of G. inflata led to the isolation of 8-prenylapigenin (3). Surprisingly, a commercial batch of 3 was devoid of estrogenic activity. Quality control by MS and qNMR revealed an incorrect compound, 4'- O-methylbroussochalcone B (10), illustrating the importance of both structural and purity verification prior to any biological investigations. Authentic and pure 3 displayed 14-fold preferential ERβ agonist activity. Quantitative analyses revealed that 3 was 33 times more concentrated in G. inflata compared to the other medicinal licorice extracts. These data suggest that standardization of G. inflata to 3 might enhance the safety and efficacy of G. inflata supplements used for postmenopausal women's health.
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
22.48
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
5.66
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
6.45
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-7.01
%
|
|
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media using NBS plates, by Resazurin F(560/590)
|
Staphylococcus aureus subsp. aureus
|
3.06
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by Resazurin F(560/590)
|
Acinetobacter baumannii
|
1.42
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by Resazurin F(560/590)
|
Escherichia coli
|
2.99
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-27.03
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of yeast alpha-glucosidase at 50 uM using p-nitrophenyl-alpha-D-glucopyranoside as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by microplate reader analysis
|
Saccharomyces cerevisiae
|
70.0
%
|
|
Journal : J Nat Prod
Title : Anti-inflammatory and α-Glucosidase Inhibitory Activities of Labdane and Norlabdane Diterpenoids from the Rhizomes of Amomum villosum.
Year : 2019
Volume : 82
Issue : 11
First Page : 2963
Last Page : 2971
Authors : Yin H, Dan WJ, Fan BY, Guo C, Wu K, Li D, Xian KF, Pescitelli G, Gao JM.
Abstract : A new tetranorditerpenoid (1), two new labdane diterpenoids (2, 3), and nine known analogues (4-12) were isolated from the rhizomes of Amomum villosum var. xanthioides. Compound 1 is an unprecedented rearranged tetranorlabdane diterpenoid, featuring a 6/6/5 fused tricarbocyclic skeleton with an α,β-unsaturated cyclopentenone unit, while 2 is a structurally rare labdane diterpenoid carrying a five-membered cyclic anhydride moiety. Their structures and absolute configurations were established on the basis of spectroscopic data and the experimental and calculated ECD data. Compound 4 showed inhibitory activity against nitric oxide production, with an IC50 value of 2.4 μM, and also inhibited α-glucosidase activity (IC50 = 10.0 μM).
|
Inhibition of F1F0-ATP synthase in Escherichia coli after 60 mins relative to control
|
Escherichia coli
|
40.0
%
|
|
Journal : Eur J Med Chem
Title : Recent advancements in mechanistic studies and structure activity relationship of FoF1 ATP synthase inhibitor as antimicrobial agent.
Year : 2019
Volume : 182
First Page : 111644
Last Page : 111644
Authors : Narang R, Kumar R, Kalra S, Nayak SK, Khatik GL, Kumar GN, Sudhakar K, Singh SK.
Abstract : The emergence of drug resistance in infectious microbial strains can be overcome by development of novel drug molecules against unexploited microbial target. The success of Bedaquiline in recent years, as FoF1 ATP synthase inhibitor against XDR and MDR mycobacterium strains, has resulted in further exploration to identify more potent and safe drug molecules against resistant strains. FoF1 ATP synthase is the main energy production enzyme in almost all eukaryotes and prokaryotes. Development of bacterial ATP synthase inhibitors is a safe approach, without causing harm to mammalian cells due to structural difference between bacterial and mammalian ATP synthase target sites. This review emphasizes on providing the structural insights for FoF1 ATP synthase of different prokaryotes and will help in the design of new potent antimicrobial agents with better efficacy. Further, applications of synthetic and natural active antimicrobial ATP synthase inhibitors, reported by different research groups are summarized. Their SAR and mode of actions are also analysed.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
22.58
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
1.568
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.35
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.02
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.35
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.02
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of recombinant human PTP1B (1 to 321 residues) expressed in Escherichia coli at 10 uM using p-nitrophenyl phosphate as substrate incubated for 30 mins relative to control
|
Homo sapiens
|
60.0
%
|
|
Journal : J Nat Prod
Title : Prenylated Phenolic Compounds from the Aerial Parts of <i>Glycyrrhiza uralensis</i> as PTP1B and α-Glucosidase Inhibitors.
Year : 2020
Volume : 83
Issue : 4
First Page : 814
Last Page : 824
Authors : Fan JR, Kuang Y, Dong ZY, Yi Y, Zhou YX, Li B, Qiao X, Ye M.
Abstract : <i>Glycyrrhiza uralensis</i> (liquorice) is a well-known medicinal plant. Its roots and rhizomes are used as the popular Chinese herbal medicine Gan-Cao. An ethanol extract of the aerial parts of <i>G. uralensis</i> showed antidiabetic effects on db/db mice. It decreased the blood glucose level by 30.3% and increased the serum insulin level by 41.8% compared to the control group. Eighty-six phenolic compounds (<b>1</b>-<b>86</b>) were obtained from the aerial parts, including the new prenylated isoflavanones (<b>1</b>-<b>5</b>), isoflavans (<b>6</b>-<b>9</b>), and a 2-phenylbenzofuran (<b>10</b>). The structures were identified by NMR and HRESIMS data analyses, and the absolute configurations were established by comparing the calculated and experimental ECD spectroscopic data. Compounds <b>2</b>, <b>6</b>, and <b>10</b> inhibited PTP1B with IC<sub>50</sub> values of 5.9, 6.7, and 5.3 μM, respectively. Compound <b>2</b> and the known compounds glycycoumarin (<b>76</b>) and glyurallin A (<b>79</b>) inhibited α-glucosidase with IC<sub>50</sub> values of 20.1, 0.1, and 0.3 μM, respectively. Compound <b>4</b> at 10 μM increased the glucose uptake rate to 95% in an insulin resistance HepG2 cell model (<i>p</i> < 0.01).
|
Inhibition of alpha-Glucosidase (unknown origin) at 10 uM using pNPG as substrate incubated for 30 mins relative to control
|
Homo sapiens
|
58.4
%
|
|
Journal : J Nat Prod
Title : Prenylated Phenolic Compounds from the Aerial Parts of <i>Glycyrrhiza uralensis</i> as PTP1B and α-Glucosidase Inhibitors.
Year : 2020
Volume : 83
Issue : 4
First Page : 814
Last Page : 824
Authors : Fan JR, Kuang Y, Dong ZY, Yi Y, Zhou YX, Li B, Qiao X, Ye M.
Abstract : <i>Glycyrrhiza uralensis</i> (liquorice) is a well-known medicinal plant. Its roots and rhizomes are used as the popular Chinese herbal medicine Gan-Cao. An ethanol extract of the aerial parts of <i>G. uralensis</i> showed antidiabetic effects on db/db mice. It decreased the blood glucose level by 30.3% and increased the serum insulin level by 41.8% compared to the control group. Eighty-six phenolic compounds (<b>1</b>-<b>86</b>) were obtained from the aerial parts, including the new prenylated isoflavanones (<b>1</b>-<b>5</b>), isoflavans (<b>6</b>-<b>9</b>), and a 2-phenylbenzofuran (<b>10</b>). The structures were identified by NMR and HRESIMS data analyses, and the absolute configurations were established by comparing the calculated and experimental ECD spectroscopic data. Compounds <b>2</b>, <b>6</b>, and <b>10</b> inhibited PTP1B with IC<sub>50</sub> values of 5.9, 6.7, and 5.3 μM, respectively. Compound <b>2</b> and the known compounds glycycoumarin (<b>76</b>) and glyurallin A (<b>79</b>) inhibited α-glucosidase with IC<sub>50</sub> values of 20.1, 0.1, and 0.3 μM, respectively. Compound <b>4</b> at 10 μM increased the glucose uptake rate to 95% in an insulin resistance HepG2 cell model (<i>p</i> < 0.01).
|
Inhibition of electric eel AChE at 100 uM using acetylthiocholine iodide as substrate by Ellman's colorimetric analysis relative to control
|
Electrophorus electricus
|
12.0
%
|
|
Journal : J Med Chem
Title : Glucosylpolyphenols as Inhibitors of Aβ-Induced Fyn Kinase Activation and Tau Phosphorylation: Synthesis, Membrane Permeability, and Exploratory Target Assessment within the Scope of Type 2 Diabetes and Alzheimer's Disease.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 11663
Last Page : 11690
Authors : de Matos AM,Blázquez-Sánchez MT,Bento-Oliveira A,de Almeida RFM,Nunes R,Lopes PEM,Machuqueiro M,Cristóvão JS,Gomes CM,Souza CS,El Idrissi IG,Colabufo NA,Diniz A,Marcelo F,Oliveira MC,López Ó,Fernandez-Bolaños JG,Dätwyler P,Ernst B,Ning K,Garwood C,Chen B,Rauter AP
Abstract : Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and β-glucosidase. Both compounds are nontoxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity, and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.
|
Inhibition of equine serum BuChE at 100 uM using butyrylthiocholine iodide as substrate by Ellman's colorimetric analysis relative to control
|
Equus caballus
|
41.0
%
|
|
Journal : J Med Chem
Title : Glucosylpolyphenols as Inhibitors of Aβ-Induced Fyn Kinase Activation and Tau Phosphorylation: Synthesis, Membrane Permeability, and Exploratory Target Assessment within the Scope of Type 2 Diabetes and Alzheimer's Disease.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 11663
Last Page : 11690
Authors : de Matos AM,Blázquez-Sánchez MT,Bento-Oliveira A,de Almeida RFM,Nunes R,Lopes PEM,Machuqueiro M,Cristóvão JS,Gomes CM,Souza CS,El Idrissi IG,Colabufo NA,Diniz A,Marcelo F,Oliveira MC,López Ó,Fernandez-Bolaños JG,Dätwyler P,Ernst B,Ning K,Garwood C,Chen B,Rauter AP
Abstract : Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and β-glucosidase. Both compounds are nontoxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity, and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.
|
Competitive inhibition of almond beta-glucosidase at 100 uM using p-nitrophenyl glycosides as substrate measured for 125 secs by spectrophotometry analysis relative to control
|
Prunus dulcis
|
44.0
%
|
|
Journal : J Med Chem
Title : Glucosylpolyphenols as Inhibitors of Aβ-Induced Fyn Kinase Activation and Tau Phosphorylation: Synthesis, Membrane Permeability, and Exploratory Target Assessment within the Scope of Type 2 Diabetes and Alzheimer's Disease.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 11663
Last Page : 11690
Authors : de Matos AM,Blázquez-Sánchez MT,Bento-Oliveira A,de Almeida RFM,Nunes R,Lopes PEM,Machuqueiro M,Cristóvão JS,Gomes CM,Souza CS,El Idrissi IG,Colabufo NA,Diniz A,Marcelo F,Oliveira MC,López Ó,Fernandez-Bolaños JG,Dätwyler P,Ernst B,Ning K,Garwood C,Chen B,Rauter AP
Abstract : Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and β-glucosidase. Both compounds are nontoxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity, and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.
|
Uncompetitive inhibition of Saccharomyces cerevisiae alpha-glucosidase at 100 uM using p-nitrophenyl glycosides as substrate measured for 125 secs by spectrophotometry analysis relative to control
|
Saccharomyces cerevisiae
|
84.0
%
|
|
Journal : J Med Chem
Title : Glucosylpolyphenols as Inhibitors of Aβ-Induced Fyn Kinase Activation and Tau Phosphorylation: Synthesis, Membrane Permeability, and Exploratory Target Assessment within the Scope of Type 2 Diabetes and Alzheimer's Disease.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 11663
Last Page : 11690
Authors : de Matos AM,Blázquez-Sánchez MT,Bento-Oliveira A,de Almeida RFM,Nunes R,Lopes PEM,Machuqueiro M,Cristóvão JS,Gomes CM,Souza CS,El Idrissi IG,Colabufo NA,Diniz A,Marcelo F,Oliveira MC,López Ó,Fernandez-Bolaños JG,Dätwyler P,Ernst B,Ning K,Garwood C,Chen B,Rauter AP
Abstract : Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and β-glucosidase. Both compounds are nontoxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity, and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.
|
Cytotoxicity against mouse B16-BL6 cells assessed as reduction in cell viability incubated for 5 days by MTT assay
|
Mus msuculus
|
4.18
ug.mL-1
|
|
Journal : Bioorg Med Chem
Title : Insights into tyrosinase inhibition by compounds isolated from Greyia radlkoferi Szyszyl using biological activity, molecular docking and gene expression analysis.
Year : 2016
Volume : 24
Issue : 22.0
First Page : 5953
Last Page : 5959
Authors : Lall N,Mogapi E,de Canha MN,Crampton B,Nqephe M,Hussein AA,Kumar V
Abstract : Greyia radlkoferi ethanol extract and its five compounds were tested for their inhibitory activity against the mushroom tyrosinase enzyme and melanin production on melanocytes. The crude extract showed significant tyrosinase inhibition with IC of 17.96μg/ml. This is the first report of the isolation of these 5 compounds from Greyia radlkoferi. 2',4',6'-Trihydroxydihydrochalcone showed the highest tyrosinase inhibition at 17.70μg/ml (68.48μM), with low toxicity when compared with crude extract. This compound is therefore, a key component in the crude extract, which is responsible for tyrosinase inhibitory activity. The RT-qPCR indicated that the mechanism of action is most likely post transcriptional. Further, the molecular docking study showed that tyrosinase inhibitory activity depends on interaction of the compound with Cu ions at the active site. This is the first report of the tyrosinase inhibitory activity of the G. radlkoferi extract and molecular insights on interaction of its compounds with Cu ions as the driving factor for tyrosinase inhibition. These results suggest that the extract of G. radlkoferi and the compound 2',4',6'-trihydroxydihydrochalcone have great potential to be further developed as pharmaceutical or cosmetic agents for use against dermatological disorders associated with melanin.
|
Inhibition of recombinant human MEK4 (14 to 377 residues) after 5 mins by Western blot analysis
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Non-'classical' MEKs: A review of MEK3-7 inhibitors.
Year : 2020
Volume : 30
Issue : 13
First Page : 127203
Last Page : 127203
Authors : Kwong AJ,Scheidt KA
Abstract : The MAPK pathways are an enduring area of interest due to their essential roles in cell processes. Increased expression and activity can lead to a multitude of diseases, sparking research efforts in developing inhibitors against these kinases. Though great strides have been made in developing MEK1/2 inhibitors, there is a notable lack of chemical probes for MEK3-7, given their central role in stimuli response, cell growth, and development. This review summarizes the progress that has been made on developing small molecule probes for MEK3-7, the specific disease states in which they have been studied, and their potential to become novel therapeutics.
|
Inhibition of electric eel AChE at 25 uM by Ellman's method relative to control
|
Electrophorus electricus
|
5.0
%
|
|
Journal : Eur J Med Chem
Title : The development of advanced structural framework as multi-target-directed ligands for the treatment of Alzheimer's disease.
Year : 2020
Volume : 192
First Page : 112180
Last Page : 112180
Authors : Sang Z,Wang K,Shi J,Liu W,Cheng X,Zhu G,Wang Y,Zhao Y,Qiao Z,Wu A,Tan Z
Abstract : In this work, we have developed a novel series of multi-target-directed ligands to address low levels of acetylcholine (ACh), oxidative stress, metal ion dysregulation, and the misfolded proteins. Novel apigenin-donepezil derivatives, naringenin-donepezil derivatives, genistein-donepezil derivatives and chalcone-donepezil derivatives have been synthesized, in vitro results showed that TM-4 was a reversible and potent huAChE (IC = 0.36 μM) and huBChE (IC = 15.3 μM) inhibitor, and showed potent antioxidant activity (ORAC = 1.2 eq). TM-4 could significantly inhibit self-induced Aβ aggregation (IC = 3.7 μM). TM-4 was also an ideal neuroprotectant, potential metal chelation agent, and it could inhibit and disaggregate huAChE-induced and Cu-induced Aβ aggregation. Moreover, TM-4 could activate UPS degradation pathway in HT22 cells and induce autophagy on U87 cells to clear abnormal proteins associated with AD. More importantly, TM-4 could cross BBB in vitro assay. In addition, in vivo assay revealed that TM-4 exhibited remarkable dyskinesia recovery rate and response efficiency on AlCl-induced zebrafish AD model, and TM-4 indicated surprising protective effect on Aβ-induced vascular injury. TM-4 presented precognitive effect on scopolamine-induced memory impairment. And the regulation of multi-targets for TM-4 were further conformed through transcriptome sequencing. More interesting, the blood, urine and feces metabolism in rat and rat/human liver microsome metabolism towards TM-4 were also investigated. Overall, TM-4 is a promising multi-function candidate for the development of drugs to Alzheimer's disease.
|
Inhibition of equine serum BChE at 25 uM by Ellman's method relative to control
|
Equus caballus
|
5.0
%
|
|
Journal : Eur J Med Chem
Title : The development of advanced structural framework as multi-target-directed ligands for the treatment of Alzheimer's disease.
Year : 2020
Volume : 192
First Page : 112180
Last Page : 112180
Authors : Sang Z,Wang K,Shi J,Liu W,Cheng X,Zhu G,Wang Y,Zhao Y,Qiao Z,Wu A,Tan Z
Abstract : In this work, we have developed a novel series of multi-target-directed ligands to address low levels of acetylcholine (ACh), oxidative stress, metal ion dysregulation, and the misfolded proteins. Novel apigenin-donepezil derivatives, naringenin-donepezil derivatives, genistein-donepezil derivatives and chalcone-donepezil derivatives have been synthesized, in vitro results showed that TM-4 was a reversible and potent huAChE (IC = 0.36 μM) and huBChE (IC = 15.3 μM) inhibitor, and showed potent antioxidant activity (ORAC = 1.2 eq). TM-4 could significantly inhibit self-induced Aβ aggregation (IC = 3.7 μM). TM-4 was also an ideal neuroprotectant, potential metal chelation agent, and it could inhibit and disaggregate huAChE-induced and Cu-induced Aβ aggregation. Moreover, TM-4 could activate UPS degradation pathway in HT22 cells and induce autophagy on U87 cells to clear abnormal proteins associated with AD. More importantly, TM-4 could cross BBB in vitro assay. In addition, in vivo assay revealed that TM-4 exhibited remarkable dyskinesia recovery rate and response efficiency on AlCl-induced zebrafish AD model, and TM-4 indicated surprising protective effect on Aβ-induced vascular injury. TM-4 presented precognitive effect on scopolamine-induced memory impairment. And the regulation of multi-targets for TM-4 were further conformed through transcriptome sequencing. More interesting, the blood, urine and feces metabolism in rat and rat/human liver microsome metabolism towards TM-4 were also investigated. Overall, TM-4 is a promising multi-function candidate for the development of drugs to Alzheimer's disease.
|
Inhibition of AChE in human erythrocytes at 25 uM by Ellman's method relative to control
|
Homo sapiens
|
5.0
%
|
|
Journal : Eur J Med Chem
Title : The development of advanced structural framework as multi-target-directed ligands for the treatment of Alzheimer's disease.
Year : 2020
Volume : 192
First Page : 112180
Last Page : 112180
Authors : Sang Z,Wang K,Shi J,Liu W,Cheng X,Zhu G,Wang Y,Zhao Y,Qiao Z,Wu A,Tan Z
Abstract : In this work, we have developed a novel series of multi-target-directed ligands to address low levels of acetylcholine (ACh), oxidative stress, metal ion dysregulation, and the misfolded proteins. Novel apigenin-donepezil derivatives, naringenin-donepezil derivatives, genistein-donepezil derivatives and chalcone-donepezil derivatives have been synthesized, in vitro results showed that TM-4 was a reversible and potent huAChE (IC = 0.36 μM) and huBChE (IC = 15.3 μM) inhibitor, and showed potent antioxidant activity (ORAC = 1.2 eq). TM-4 could significantly inhibit self-induced Aβ aggregation (IC = 3.7 μM). TM-4 was also an ideal neuroprotectant, potential metal chelation agent, and it could inhibit and disaggregate huAChE-induced and Cu-induced Aβ aggregation. Moreover, TM-4 could activate UPS degradation pathway in HT22 cells and induce autophagy on U87 cells to clear abnormal proteins associated with AD. More importantly, TM-4 could cross BBB in vitro assay. In addition, in vivo assay revealed that TM-4 exhibited remarkable dyskinesia recovery rate and response efficiency on AlCl-induced zebrafish AD model, and TM-4 indicated surprising protective effect on Aβ-induced vascular injury. TM-4 presented precognitive effect on scopolamine-induced memory impairment. And the regulation of multi-targets for TM-4 were further conformed through transcriptome sequencing. More interesting, the blood, urine and feces metabolism in rat and rat/human liver microsome metabolism towards TM-4 were also investigated. Overall, TM-4 is a promising multi-function candidate for the development of drugs to Alzheimer's disease.
|
Inhibition of human serum BChE at 25 uM by Ellman's method relative to control
|
Homo sapiens
|
5.0
%
|
|
Journal : Eur J Med Chem
Title : The development of advanced structural framework as multi-target-directed ligands for the treatment of Alzheimer's disease.
Year : 2020
Volume : 192
First Page : 112180
Last Page : 112180
Authors : Sang Z,Wang K,Shi J,Liu W,Cheng X,Zhu G,Wang Y,Zhao Y,Qiao Z,Wu A,Tan Z
Abstract : In this work, we have developed a novel series of multi-target-directed ligands to address low levels of acetylcholine (ACh), oxidative stress, metal ion dysregulation, and the misfolded proteins. Novel apigenin-donepezil derivatives, naringenin-donepezil derivatives, genistein-donepezil derivatives and chalcone-donepezil derivatives have been synthesized, in vitro results showed that TM-4 was a reversible and potent huAChE (IC = 0.36 μM) and huBChE (IC = 15.3 μM) inhibitor, and showed potent antioxidant activity (ORAC = 1.2 eq). TM-4 could significantly inhibit self-induced Aβ aggregation (IC = 3.7 μM). TM-4 was also an ideal neuroprotectant, potential metal chelation agent, and it could inhibit and disaggregate huAChE-induced and Cu-induced Aβ aggregation. Moreover, TM-4 could activate UPS degradation pathway in HT22 cells and induce autophagy on U87 cells to clear abnormal proteins associated with AD. More importantly, TM-4 could cross BBB in vitro assay. In addition, in vivo assay revealed that TM-4 exhibited remarkable dyskinesia recovery rate and response efficiency on AlCl-induced zebrafish AD model, and TM-4 indicated surprising protective effect on Aβ-induced vascular injury. TM-4 presented precognitive effect on scopolamine-induced memory impairment. And the regulation of multi-targets for TM-4 were further conformed through transcriptome sequencing. More interesting, the blood, urine and feces metabolism in rat and rat/human liver microsome metabolism towards TM-4 were also investigated. Overall, TM-4 is a promising multi-function candidate for the development of drugs to Alzheimer's disease.
|
Inhibition of cytochrome c (unknown origin) assessed as reduction in cyt c-CL complex formation at 10 uM incubated for 15 mins in presence of cardiolipin by Trp-59 fluorescence assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg Med Chem
Title : A role of flavonoids in cytochrome c-cardiolipin interactions.
Year : 2021
Volume : 33
First Page : 116043
Last Page : 116043
Authors : Rice M,Wong B,Oja M,Samuels K,Williams AK,Fong J,Sapse AM,Maran U,Korobkova EA
Abstract : The processes preceding the detachment of cytochrome c (cyt c) from the inner mitochondrial membrane in intrinsic apoptosis involve peroxidation of cardiolipin (CL) catalyzed by cyt c-CL complex. In the present work, we studied the effect of 17 dietary flavonoids on the peroxidase activity of cyt c bound to liposomes. Specifically, we explored the relationship between peroxidase activity and flavonoids' (1) potential to modulate cyt c unfolding, (2) effect on the oxidation state of heme iron, (3) membrane permeability, (4) membrane binding energy, and (5) structure. The measurements revealed that flavones, flavonols, and flavanols were the strongest, while isoflavones were the weakest inhibitors of the oxidation. Flavonoids' peroxidase inhibition activity correlated positively with their potential to suppress Trp-59 fluorescence in cyt c as well as the number of OH groups. Hydrophilic flavonoids, such as catechin, having the lowest membrane permeability and the strongest binding with phosphocholine (PC) based on the quantum chemical calculations exhibited the strongest inhibition of Amplex Red (AR) peroxidation, suggesting a membrane-protective function of flavonoids at the surface. The results of the present research specify basic principles for the design of molecules that will control the catalytic oxidation of lipids in mitochondrial membranes. These principles take into account the number of hydroxyl groups and hydrophilicity of flavonoids.
|
Inhibition of cytochrome c (unknown origin) assessed as reduction in cyt c-CL peroxidase activity at 10 uM up to 20 mins in presence of cardiolipin by Amplex red staining based fluorescence assay relative to control
|
Homo sapiens
|
51.0
%
|
|
Journal : Bioorg Med Chem
Title : A role of flavonoids in cytochrome c-cardiolipin interactions.
Year : 2021
Volume : 33
First Page : 116043
Last Page : 116043
Authors : Rice M,Wong B,Oja M,Samuels K,Williams AK,Fong J,Sapse AM,Maran U,Korobkova EA
Abstract : The processes preceding the detachment of cytochrome c (cyt c) from the inner mitochondrial membrane in intrinsic apoptosis involve peroxidation of cardiolipin (CL) catalyzed by cyt c-CL complex. In the present work, we studied the effect of 17 dietary flavonoids on the peroxidase activity of cyt c bound to liposomes. Specifically, we explored the relationship between peroxidase activity and flavonoids' (1) potential to modulate cyt c unfolding, (2) effect on the oxidation state of heme iron, (3) membrane permeability, (4) membrane binding energy, and (5) structure. The measurements revealed that flavones, flavonols, and flavanols were the strongest, while isoflavones were the weakest inhibitors of the oxidation. Flavonoids' peroxidase inhibition activity correlated positively with their potential to suppress Trp-59 fluorescence in cyt c as well as the number of OH groups. Hydrophilic flavonoids, such as catechin, having the lowest membrane permeability and the strongest binding with phosphocholine (PC) based on the quantum chemical calculations exhibited the strongest inhibition of Amplex Red (AR) peroxidation, suggesting a membrane-protective function of flavonoids at the surface. The results of the present research specify basic principles for the design of molecules that will control the catalytic oxidation of lipids in mitochondrial membranes. These principles take into account the number of hydroxyl groups and hydrophilicity of flavonoids.
|
Inhibition of cytochrome c (unknown origin) assessed as reduction reduction of cyt c from its ferric state to ferrous state at 10 uM incubated for 20 mins in presence of cardiolipin by UV-vis Spectrophotometric assay relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : Bioorg Med Chem
Title : A role of flavonoids in cytochrome c-cardiolipin interactions.
Year : 2021
Volume : 33
First Page : 116043
Last Page : 116043
Authors : Rice M,Wong B,Oja M,Samuels K,Williams AK,Fong J,Sapse AM,Maran U,Korobkova EA
Abstract : The processes preceding the detachment of cytochrome c (cyt c) from the inner mitochondrial membrane in intrinsic apoptosis involve peroxidation of cardiolipin (CL) catalyzed by cyt c-CL complex. In the present work, we studied the effect of 17 dietary flavonoids on the peroxidase activity of cyt c bound to liposomes. Specifically, we explored the relationship between peroxidase activity and flavonoids' (1) potential to modulate cyt c unfolding, (2) effect on the oxidation state of heme iron, (3) membrane permeability, (4) membrane binding energy, and (5) structure. The measurements revealed that flavones, flavonols, and flavanols were the strongest, while isoflavones were the weakest inhibitors of the oxidation. Flavonoids' peroxidase inhibition activity correlated positively with their potential to suppress Trp-59 fluorescence in cyt c as well as the number of OH groups. Hydrophilic flavonoids, such as catechin, having the lowest membrane permeability and the strongest binding with phosphocholine (PC) based on the quantum chemical calculations exhibited the strongest inhibition of Amplex Red (AR) peroxidation, suggesting a membrane-protective function of flavonoids at the surface. The results of the present research specify basic principles for the design of molecules that will control the catalytic oxidation of lipids in mitochondrial membranes. These principles take into account the number of hydroxyl groups and hydrophilicity of flavonoids.
