|
Inhibition of human placental microsome CYP19
|
Homo sapiens
|
52.48
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselective nonsteroidal aromatase inhibitors identified through a multidisciplinary medicinal chemistry approach.
Year : 2005
Volume : 48
Issue : 23
First Page : 7282
Last Page : 7289
Authors : Cavalli A, Bisi A, Bertucci C, Rosini C, Paluszcak A, Gobbi S, Giorgio E, Rampa A, Belluti F, Piazzi L, Valenti P, Hartmann RW, Recanatini M.
Abstract : To identify enantioselective nonsteroidal aromatase inhibitors, a multidisciplinary medicinal chemistry approach was pursued. First, our earlier CoMFA model [Bioorg. Med. Chem. 1998,6, 377-388] was extended taking purposely into account previously discovered enantioselective aromatase inhibitors. The 3D QSAR model was then exploited to design chiral ligands, whose configurational assignment was obtained, after HPLC separation, by means of a combination of circular dichroism measurements and time dependent density functional calculations. Finally, the new enantiomeric inhibitors were separately tested to ascertain both their potency against the cytochrome P450 aromatase (CYP19; EC 1.14.14.1), and their selectivity relative to another enzyme of the P450 family. A satisfactory agreement between experimental and predicted data allowed us to assert that a properly built "enantioselective CoMFA model" might constitute a useful tool for addressing enantioselective ligands design.
|
Inhibition of human recombinant aromatase at 300 nM after 30 mins relative to control
|
Homo sapiens
|
89.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of DL-standishinal and its related compounds for the studies on structure-activity relationship of inhibitory activity against aromatase.
Year : 2007
Volume : 15
Issue : 7
First Page : 2736
Last Page : 2748
Authors : Katoh T, Akagi T, Noguchi C, Kajimoto T, Node M, Tanaka R, Nishizawa née Iwamoto M, Ohtsu H, Suzuki N, Saito K.
Abstract : DL-Standishinal (1), an aromatase inhibitor isolated from Thuja standishii, was synthesized in 15 steps from p-formylanisole via aldol reaction of 12-hydroxy-6,7-secoabieta-8,11,13-trien-6,7-dial (2). In the present study, we found that the aldol condensation of 2 proceeded in excellent yield with the protonic catalyst such as d-camphorsulfonic acid in CH(2)Cl(2). Moreover, structure-activity relationship of 1 and its related compounds was studied and it was revealed that the isomers having cis-configuration on the A/B-ring generally exhibited more potent inhibitory activities against aromatase than those with trans-configuration.
|
Inhibition of human recombinant aromatase at 1 uM after 30 mins relative to control
|
Homo sapiens
|
91.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of DL-standishinal and its related compounds for the studies on structure-activity relationship of inhibitory activity against aromatase.
Year : 2007
Volume : 15
Issue : 7
First Page : 2736
Last Page : 2748
Authors : Katoh T, Akagi T, Noguchi C, Kajimoto T, Node M, Tanaka R, Nishizawa née Iwamoto M, Ohtsu H, Suzuki N, Saito K.
Abstract : DL-Standishinal (1), an aromatase inhibitor isolated from Thuja standishii, was synthesized in 15 steps from p-formylanisole via aldol reaction of 12-hydroxy-6,7-secoabieta-8,11,13-trien-6,7-dial (2). In the present study, we found that the aldol condensation of 2 proceeded in excellent yield with the protonic catalyst such as d-camphorsulfonic acid in CH(2)Cl(2). Moreover, structure-activity relationship of 1 and its related compounds was studied and it was revealed that the isomers having cis-configuration on the A/B-ring generally exhibited more potent inhibitory activities against aromatase than those with trans-configuration.
|
Inhibition of human recombinant aromatase at 3 uM after 30 mins relative to control
|
Homo sapiens
|
83.8
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of DL-standishinal and its related compounds for the studies on structure-activity relationship of inhibitory activity against aromatase.
Year : 2007
Volume : 15
Issue : 7
First Page : 2736
Last Page : 2748
Authors : Katoh T, Akagi T, Noguchi C, Kajimoto T, Node M, Tanaka R, Nishizawa née Iwamoto M, Ohtsu H, Suzuki N, Saito K.
Abstract : DL-Standishinal (1), an aromatase inhibitor isolated from Thuja standishii, was synthesized in 15 steps from p-formylanisole via aldol reaction of 12-hydroxy-6,7-secoabieta-8,11,13-trien-6,7-dial (2). In the present study, we found that the aldol condensation of 2 proceeded in excellent yield with the protonic catalyst such as d-camphorsulfonic acid in CH(2)Cl(2). Moreover, structure-activity relationship of 1 and its related compounds was studied and it was revealed that the isomers having cis-configuration on the A/B-ring generally exhibited more potent inhibitory activities against aromatase than those with trans-configuration.
|
Inhibition of human recombinant aromatase at 10 uM after 30 mins relative to control
|
Homo sapiens
|
92.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of DL-standishinal and its related compounds for the studies on structure-activity relationship of inhibitory activity against aromatase.
Year : 2007
Volume : 15
Issue : 7
First Page : 2736
Last Page : 2748
Authors : Katoh T, Akagi T, Noguchi C, Kajimoto T, Node M, Tanaka R, Nishizawa née Iwamoto M, Ohtsu H, Suzuki N, Saito K.
Abstract : DL-Standishinal (1), an aromatase inhibitor isolated from Thuja standishii, was synthesized in 15 steps from p-formylanisole via aldol reaction of 12-hydroxy-6,7-secoabieta-8,11,13-trien-6,7-dial (2). In the present study, we found that the aldol condensation of 2 proceeded in excellent yield with the protonic catalyst such as d-camphorsulfonic acid in CH(2)Cl(2). Moreover, structure-activity relationship of 1 and its related compounds was studied and it was revealed that the isomers having cis-configuration on the A/B-ring generally exhibited more potent inhibitory activities against aromatase than those with trans-configuration.
|
Inhibition of aromatase in Wistar rat assessed as reduction of PMSG-stimulated plasma estradiol level at 10 mg/kg, po after 3 hrs
|
Rattus norvegicus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Dual aromatase-steroid sulfatase inhibitors.
Year : 2007
Volume : 50
Issue : 15
First Page : 3540
Last Page : 3560
Authors : Woo LW, Bubert C, Sutcliffe OB, Smith A, Chander SK, Mahon MF, Purohit A, Reed MJ, Potter BV.
Abstract : By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.
|
Inhibition of aromatase in Wistar rat assessed as reduction of PMSG-stimulated plasma estradiol level at 10 mg/kg, po after 24 hrs
|
Rattus norvegicus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Dual aromatase-steroid sulfatase inhibitors.
Year : 2007
Volume : 50
Issue : 15
First Page : 3540
Last Page : 3560
Authors : Woo LW, Bubert C, Sutcliffe OB, Smith A, Chander SK, Mahon MF, Purohit A, Reed MJ, Potter BV.
Abstract : By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.
|
Inhibition of steroid sulfatase in Wistar rat assessed as reduction of PMSG-stimulated plasma estradiol level at 10 mg/kg, po after 3 hrs
|
Rattus norvegicus
|
3.0
%
|
|
Journal : J. Med. Chem.
Title : Dual aromatase-steroid sulfatase inhibitors.
Year : 2007
Volume : 50
Issue : 15
First Page : 3540
Last Page : 3560
Authors : Woo LW, Bubert C, Sutcliffe OB, Smith A, Chander SK, Mahon MF, Purohit A, Reed MJ, Potter BV.
Abstract : By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.
|
Inhibition of steroid sulfatase in Wistar rat assessed as reduction of PMSG-stimulated plasma estradiol level at 10 mg/kg, po after 24 hrs
|
Rattus norvegicus
|
6.0
%
|
|
Journal : J. Med. Chem.
Title : Dual aromatase-steroid sulfatase inhibitors.
Year : 2007
Volume : 50
Issue : 15
First Page : 3540
Last Page : 3560
Authors : Woo LW, Bubert C, Sutcliffe OB, Smith A, Chander SK, Mahon MF, Purohit A, Reed MJ, Potter BV.
Abstract : By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.
|
Inhibition of aromatase activity in human JEG3 cells
|
Homo sapiens
|
0.89
nM
|
|
Journal : J. Med. Chem.
Title : Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: synthesis, absolute configuration, and in vitro activity.
Year : 2008
Volume : 51
Issue : 14
First Page : 4226
Last Page : 4238
Authors : Wood PM, Woo LW, Labrosse JR, Trusselle MN, Abbate S, Longhi G, Castiglioni E, Lebon F, Purohit A, Reed MJ, Potter BV.
Abstract : To explore aromatase inhibition and to broaden the structural diversity of dual aromatase-sulfatase inhibitors (DASIs), we introduced the steroid sulfatase (STS) inhibitory pharmacophore to letrozole. Letrozole derivatives were prepared bearing bis-sulfamates or mono-sulfamates with or without adjacent substituents. The most potent of the achiral and racemic aromatase inhibitor was 40 (IC 50 = 3.0 nM). Its phenolic precursor 39 was separated by chiral HPLC, and the absolute configuration of each enantiomer was determined using vibrational and electronic circular dichroism in tandem with calculations of the predicted spectra. Of the two enantiomers, ( R)-phenol ( 39a) was the most potent aromatase inhibitor (IC 50 = 0.6 nM, comparable to letrozole), whereas the ( S)-sulfamate, ( 40b) inhibited STS most potently (IC 50 = 553 nM). These results suggest that a new structural class of DASI for potential treatment of hormone-dependent breast cancer has been identified, and this is the first report of STS inhibition by an enantiopure nonsteroidal compound.
|
Inhibition of aromatase in human placental microsomes
|
Homo sapiens
|
11.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 6- or 4-functionalized indoles via a reductive cyclization approach and evaluation as aromatase inhibitors.
Year : 2008
Volume : 18
Issue : 16
First Page : 4713
Last Page : 4715
Authors : Lézé MP, Palusczak A, Hartmann RW, Le Borgne M.
Abstract : Two new series of benzonitrile derivatives on position 6 or 4 of indole ring were successfully synthesized via a Leimgruber-Batcho reaction. All the compounds were evaluated in vitro on the inhibition of aromatase (CYP19) and 17alpha-hydroxylase-C17,20-lyase (CYP17). The racemate, 4-[(1H-imidazol-1-yl)(1H-indol-4-yl)methyl]benzonitrile 9, showed high level of inhibitory activity towards CYP19 (IC(50)=11.5 nM).
|
Inhibition of human aromatase-mediated conversion of [1beta3H]androstenedione to estrone by liquid scintillation counting in presence of NADPH
|
Homo sapiens
|
6.1
nM
|
|
Journal : J. Med. Chem.
Title : Fast three dimensional pharmacophore virtual screening of new potent non-steroid aromatase inhibitors.
Year : 2009
Volume : 52
Issue : 1
First Page : 143
Last Page : 150
Authors : Neves MA, Dinis TC, Colombo G, Sá e Melo ML.
Abstract : Suppression of estrogen biosynthesis by aromatase inhibition is an effective approach for the treatment of hormone sensitive breast cancer. Third generation non-steroid aromatase inhibitors have shown important benefits in recent clinical trials with postmenopausal women. In this study we have developed a new ligand-based strategy combining important pharmacophoric and structural features according to the postulated aromatase binding mode, useful for the virtual screening of new potent non-steroid inhibitors. A small subset of promising drug candidates was identified from the large NCI database, and their antiaromatase activity was assessed on an in vitro biochemical assay with aromatase extracted from human term placenta. New potent aromatase inhibitors were discovered to be active in the low nanomolar range, and a common binding mode was proposed. These results confirm the potential of our methodology for a fast in silico high-throughput screening of potent non-steroid aromatase inhibitors.
|
Inhibition of human aromatase-mediated conversion of [1beta3H]androstenedione to estrone by Lineweaver-Burke plot in presence of NADPH
|
Homo sapiens
|
2.2
nM
|
|
Journal : J. Med. Chem.
Title : Fast three dimensional pharmacophore virtual screening of new potent non-steroid aromatase inhibitors.
Year : 2009
Volume : 52
Issue : 1
First Page : 143
Last Page : 150
Authors : Neves MA, Dinis TC, Colombo G, Sá e Melo ML.
Abstract : Suppression of estrogen biosynthesis by aromatase inhibition is an effective approach for the treatment of hormone sensitive breast cancer. Third generation non-steroid aromatase inhibitors have shown important benefits in recent clinical trials with postmenopausal women. In this study we have developed a new ligand-based strategy combining important pharmacophoric and structural features according to the postulated aromatase binding mode, useful for the virtual screening of new potent non-steroid inhibitors. A small subset of promising drug candidates was identified from the large NCI database, and their antiaromatase activity was assessed on an in vitro biochemical assay with aromatase extracted from human term placenta. New potent aromatase inhibitors were discovered to be active in the low nanomolar range, and a common binding mode was proposed. These results confirm the potential of our methodology for a fast in silico high-throughput screening of potent non-steroid aromatase inhibitors.
|
Inhibition of aromatase in human JEG3 cells by scintillation spectrometry
|
Homo sapiens
|
0.89
nM
|
|
Journal : J. Med. Chem.
Title : Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template.
Year : 2010
Volume : 53
Issue : 5
First Page : 2155
Last Page : 2170
Authors : Woo LW, Jackson T, Putey A, Cozier G, Leonard P, Acharya KR, Chander SK, Purohit A, Reed MJ, Potter BV.
Abstract : Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.
|
Inhibition of aromatase in PMSG-pretreated Wistar rat plasma at 0.1 mg/kg, po administered after 3 days of PMSG challenge by radioimmunoassay
|
Rattus norvegicus
|
85.0
%
|
|
Journal : J. Med. Chem.
Title : Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template.
Year : 2010
Volume : 53
Issue : 5
First Page : 2155
Last Page : 2170
Authors : Woo LW, Jackson T, Putey A, Cozier G, Leonard P, Acharya KR, Chander SK, Purohit A, Reed MJ, Potter BV.
Abstract : Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.
|
Inhibition of steroid sulfatase in PMSG-pretreated Wistar rat plasma at 0.1 mg/kg, po administered after 3 days of PMSG challenge by radioimmunoassay
|
Rattus norvegicus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template.
Year : 2010
Volume : 53
Issue : 5
First Page : 2155
Last Page : 2170
Authors : Woo LW, Jackson T, Putey A, Cozier G, Leonard P, Acharya KR, Chander SK, Purohit A, Reed MJ, Potter BV.
Abstract : Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.
|
Inhibition of human recombinant aromatase at 1 uM
|
Homo sapiens
|
91.1
%
|
|
Journal : J. Nat. Prod.
Title : The taiwaniaquinoids: a review.
Year : 2010
Volume : 73
Issue : 2
First Page : 284
Last Page : 298
Authors : Majetich G, Shimkus JM.
Abstract : A comprehensive overview of the taiwaniaquinoid family of natural products is presented. A summary of the isolation, biosynthesis, and biological activity of these compounds is followed by a discussion of various synthetic strategies to the skeletal framework and a detailed discussion of 12 published syntheses of members of this family. This review covers the literature from the discovery of the first taiwaniaquinoid in 1995 until June 2009.
|
Inhibition of human recombinant aromatase at 10 uM
|
Homo sapiens
|
87.9
%
|
|
Journal : J. Nat. Prod.
Title : The taiwaniaquinoids: a review.
Year : 2010
Volume : 73
Issue : 2
First Page : 284
Last Page : 298
Authors : Majetich G, Shimkus JM.
Abstract : A comprehensive overview of the taiwaniaquinoid family of natural products is presented. A summary of the isolation, biosynthesis, and biological activity of these compounds is followed by a discussion of various synthetic strategies to the skeletal framework and a detailed discussion of 12 published syntheses of members of this family. This review covers the literature from the discovery of the first taiwaniaquinoid in 1995 until June 2009.
|
Inhibition of human recombinant aromatase at 3 uM
|
Homo sapiens
|
87.5
%
|
|
Journal : J. Nat. Prod.
Title : The taiwaniaquinoids: a review.
Year : 2010
Volume : 73
Issue : 2
First Page : 284
Last Page : 298
Authors : Majetich G, Shimkus JM.
Abstract : A comprehensive overview of the taiwaniaquinoid family of natural products is presented. A summary of the isolation, biosynthesis, and biological activity of these compounds is followed by a discussion of various synthetic strategies to the skeletal framework and a detailed discussion of 12 published syntheses of members of this family. This review covers the literature from the discovery of the first taiwaniaquinoid in 1995 until June 2009.
|
Inhibition of human recombinant aromatase at 0.3 uM
|
Homo sapiens
|
81.7
%
|
|
Journal : J. Nat. Prod.
Title : The taiwaniaquinoids: a review.
Year : 2010
Volume : 73
Issue : 2
First Page : 284
Last Page : 298
Authors : Majetich G, Shimkus JM.
Abstract : A comprehensive overview of the taiwaniaquinoid family of natural products is presented. A summary of the isolation, biosynthesis, and biological activity of these compounds is followed by a discussion of various synthetic strategies to the skeletal framework and a detailed discussion of 12 published syntheses of members of this family. This review covers the literature from the discovery of the first taiwaniaquinoid in 1995 until June 2009.
|
Inhibition of human placental microsome CYP19
|
Homo sapiens
|
11.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacophore modeling strategies for the development of novel nonsteroidal inhibitors of human aromatase (CYP19).
Year : 2010
Volume : 20
Issue : 10
First Page : 3050
Last Page : 3064
Authors : Muftuoglu Y, Mustata G.
Abstract : The present study utilizes for the first time the structural information of aromatase, an important pharmacological target in anti-breast cancer therapy, to extract the pharmacophoric features important for interactions between the enzyme and its substrate, androstenedione. A ligand-based pharmacophore model developed from the most comprehensive list of nonsteroidal aromatase inhibitors (AIs) is described and explained, as well. This study demonstrates that the ligand-based pharmacophore model contributes to efficacy while the structure-based model contributes to specificity. It is also shown that a 'merged' model (i.e., a merged structure-based and ligand-based model) can successfully identify known AIs and differentiate between active and inactive inhibitors. Therefore, this model can be effectively used to identify the next generation of highly specific and less toxic aromatase inhibitors for breast cancer treatment.
|
Inhibition of aromatase in human placental microsomes assessed as inhibition of aromatization of [1,2,6,7-3H] androstenedione by flow scintillation analysis
|
Homo sapiens
|
18.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Lead optimization of 4-imidazolylflavans: new promising aromatase inhibitors.
Year : 2011
Volume : 46
Issue : 6
First Page : 2541
Last Page : 2545
Authors : Yahiaoui S, Pouget C, Buxeraud J, Chulia AJ, Fagnère C.
Abstract : Our previous studies have shown that several 7-substituted-4-imidazolylflavans are potent inhibitors of aromatase. These compounds were designed considering the anti-aromatase effect of some natural flavonoids and the importance of an azole ring for synthetic inhibitors such as letrozole or anastrozole towards binding to the heme iron of aromatase. In this study, we report the optimization of these lead compounds by the modulation of flavan A ring. The resulting 7,8-benzo-4-imidazolylflavans were tested in order to assess their ability to inhibit aromatase. Biological data concerning enantiomers obtained from the chiral separation of the racemate compound 4-imidazolyl-7-methoxyflavan are also presented.
|
Inhibition of human recombinant aromatase using 7-methoxy-4-trifluoromethyl coumarin as substrate by fluorimetric analysis
|
Homo sapiens
|
4.2
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of potent aromatase inhibitors by high-throughput docking.
Year : 2011
Volume : 54
Issue : 12
First Page : 4006
Last Page : 4017
Authors : Caporuscio F, Rastelli G, Imbriano C, Del Rio A.
Abstract : Cytochrome P450 aromatase catalyzes the conversion of androgen substrates into estrogens. Aromatase inhibitors (AIs) have been used as first-line drugs in the treatment of estrogen-dependent breast cancer in postmenopausal women. However, the search for new, more potent, and selective AIs still remains necessary to avoid the risk of possible resistances and reduce toxicity and side effects of current available drugs. The publication of a high resolution X-ray structure of human aromatase has opened the way to structure-based virtual screening to identify new small-molecule inhibitors with structural motifs different from all known AIs. In this context, a high-throughput docking protocol was set up and led to the identification of nanomolar AIs with new core structures.
|
Inhibition of aromatase using 7-methoxy-4-trifluoromethyl coumarin as substrate after 30 mins by fluorescence-based colorimetric analysis
|
None
|
8.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors.
Year : 2011
Volume : 46
Issue : 9
First Page : 4010
Last Page : 4024
Authors : Doiron J, Soultan AH, Richard R, Touré MM, Picot N, Richard R, Cuperlović-Culf M, Robichaud GA, Touaibia M.
Abstract : A series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the aromatase inhibitor, letrozole 1. Compound 10a, bearing a 1,2,3-triazole, is also 10000-times more tightly binding than the corresponding analogue 25 bearing a 1,2,5-triazole, which confirms the importance of a nitrogen atom at position 3 or 4 of the 5-membered ring needed for high activity. The effect on human epithelial adrenocortical carcinoma cell line (H295R) proliferation was also evaluated. The compound 10j (IC(50) = 4.64 μM), a letrozole 1 analogue bearing para-cyanophenoxymethylene-1,2,3-triazole decreased proliferation rates of H295R cells by 76 and 99% in 24 and 72 h respectively. Computer calculations, using quantum ab initio structures, suggest a possible correlation between anti-aromatase activity and the distance between the nitrogen in position 3 or 4 of triazole nitrogen and the cyano group nitrogen.
|
Inhibition of human aromatase coexpressed with P450 reductase by fluorimetry
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New aromatase inhibitors from the 3-pyridyl arylether and 1-aryl pyrrolo[2,3-c]pyridine series.
Year : 2012
Volume : 22
Issue : 5
First Page : 1860
Last Page : 1863
Authors : Stauffer F, Furet P, Floersheimer A, Lang M.
Abstract : Aromatase inhibition is the new standard of care for estrogen receptor positive breast cancer and has also potential for treatment of other diseases such as endometriosis. Simple and readily available 3-pyridyl arylethers and 1-aryl pyrrolo[2,3-c]pyridines recapitulating the key pharmacophore elements of Letrozole (1) are described and their structure-activity relationships are discussed. Potent and ligand efficient leads such as compound 23 (IC(50)=59nM on aromatase) have been identified.
|
Inhibition of human aromatase using dibenzylfluorescein substrate preincubated for 30 mins measured after 30 mins by fluorescence assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Optimization of the aromatase inhibitory activities of pyridylthiazole analogues of resveratrol.
Year : 2012
Volume : 20
Issue : 7
First Page : 2427
Last Page : 2434
Authors : Mayhoub AS, Marler L, Kondratyuk TP, Park EJ, Pezzuto JM, Cushman M.
Abstract : Aromatase is an established target not only for breast cancer chemotherapy, but also for breast cancer chemoprevention. The moderate and non-selective aromatase inhibitory activity of resveratrol (1) was improved about 100-fold by replacement of the ethylenic bridge with a thiadiazole and the phenyl rings with pyridines (e.g., compound 3). The aromatase inhibitory activity was enhanced over 6000-fold by using a 1,3-thiazole as the central ring and modifying the substituents on the 'A' ring to target the Met374 residue of aromatase. On the other hand, targeting the hydroxyl group of Thr310 by a hydrogen-bond acceptor on the 'B' ring did not improve the aromatase inhibitory activity.
|
Competitive inhibition of human aromatase using dibenzylfluorescein substrate after 10 mins preincubation measured every 10 sec for 5 mins by Michaelis-Menten and Dixon plot analysis
|
Homo sapiens
|
0.02
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Optimization of the aromatase inhibitory activities of pyridylthiazole analogues of resveratrol.
Year : 2012
Volume : 20
Issue : 7
First Page : 2427
Last Page : 2434
Authors : Mayhoub AS, Marler L, Kondratyuk TP, Park EJ, Pezzuto JM, Cushman M.
Abstract : Aromatase is an established target not only for breast cancer chemotherapy, but also for breast cancer chemoprevention. The moderate and non-selective aromatase inhibitory activity of resveratrol (1) was improved about 100-fold by replacement of the ethylenic bridge with a thiadiazole and the phenyl rings with pyridines (e.g., compound 3). The aromatase inhibitory activity was enhanced over 6000-fold by using a 1,3-thiazole as the central ring and modifying the substituents on the 'A' ring to target the Met374 residue of aromatase. On the other hand, targeting the hydroxyl group of Thr310 by a hydrogen-bond acceptor on the 'B' ring did not improve the aromatase inhibitory activity.
|
Cytotoxicity against human MCF7a cells expressing Tet-off-3betaHSD1-Arom assessed as inhibition of TST-stimulated cell proliferation measured after 10 days
|
Homo sapiens
|
0.004
nM
|
|
Journal : J. Med. Chem.
Title : Novel aromatase inhibitors by structure-guided design.
Year : 2012
Volume : 55
Issue : 19
First Page : 8464
Last Page : 8476
Authors : Ghosh D, Lo J, Morton D, Valette D, Xi J, Griswold J, Hubbell S, Egbuta C, Jiang W, An J, Davies HM.
Abstract : Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.
|
Inhibition of human placental aromatase using [3H]-1beta-androstenedione as substrate after 16 hrs by [3H]-water method
|
Homo sapiens
|
9.9
nM
|
|
Journal : J. Med. Chem.
Title : Novel aromatase inhibitors by structure-guided design.
Year : 2012
Volume : 55
Issue : 19
First Page : 8464
Last Page : 8476
Authors : Ghosh D, Lo J, Morton D, Valette D, Xi J, Griswold J, Hubbell S, Egbuta C, Jiang W, An J, Davies HM.
Abstract : Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.
|
Inhibition of human CYP17 expressed in Escherichia coli using progesterone as substrate at 2 uM
|
Homo sapiens
|
7.0
%
|
|
Journal : J. Med. Chem.
Title : Tetrahydropyrroloquinolinone type dual inhibitors of aromatase/aldosterone synthase as a novel strategy for breast cancer patients with elevated cardiovascular risks.
Year : 2013
Volume : 56
Issue : 2
First Page : 460
Last Page : 470
Authors : Yin L, Hu Q, Hartmann RW.
Abstract : The application of aromatase inhibitors to postmenopausal breast cancer patients increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concentrations of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, that is, a given substituent showed an increase in inhibition of one enzyme, while it led to a decrease for the other enzyme. The compromise of this conflict led to compounds 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, especially compound 3p, which exhibited IC(50) values of 32 and 41 nM for CYP19 and CYP11B2, respectively, and a high selectivity toward CYP17 and CYP11B1. This compound is considered as a candidate for further evaluation in vivo.
|
Inhibition of human CYP19 using [1beta-3H]androstenedione as substrate by 3H2O method
|
Homo sapiens
|
36.0
nM
|
|
Journal : J. Med. Chem.
Title : Tetrahydropyrroloquinolinone type dual inhibitors of aromatase/aldosterone synthase as a novel strategy for breast cancer patients with elevated cardiovascular risks.
Year : 2013
Volume : 56
Issue : 2
First Page : 460
Last Page : 470
Authors : Yin L, Hu Q, Hartmann RW.
Abstract : The application of aromatase inhibitors to postmenopausal breast cancer patients increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concentrations of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, that is, a given substituent showed an increase in inhibition of one enzyme, while it led to a decrease for the other enzyme. The compromise of this conflict led to compounds 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, especially compound 3p, which exhibited IC(50) values of 32 and 41 nM for CYP19 and CYP11B2, respectively, and a high selectivity toward CYP17 and CYP11B1. This compound is considered as a candidate for further evaluation in vivo.
|
Inhibition of human placental microsome aromatase after 30 mins by ELISA
|
Homo sapiens
|
16.53
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and aromatase inhibitory activities of novel indole-imidazole derivatives.
Year : 2013
Volume : 23
Issue : 6
First Page : 1760
Last Page : 1762
Authors : Wang R, Shi HF, Zhao JF, He YP, Zhang HB, Liu JP.
Abstract : A series of novel indole-imidazole derivatives have been prepared and evaluated in vitro on the aromatase inhibitory activities. The results suggested that proton or a small electron-withdrawing group at para-position of the phenyl ring would enhance the inhibitory activities and any bulky group should be avoided in order to keep a relative small volume for this kind of molecules.
|
Inhibition of aromatase (unknown origin) using 7-methoxy-4-trifluoromethylcoumarin as substrate after 30 mins by fluorimetric analysis
|
Homo sapiens
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and structure-activity relationships of azolylmethylpyrroloquinolines as nonsteroidal aromatase inhibitors.
Year : 2013
Volume : 56
Issue : 19
First Page : 7536
Last Page : 7551
Authors : Ferlin MG, Carta D, Bortolozzi R, Ghodsi R, Chimento A, Pezzi V, Moro S, Hanke N, Hartmann RW, Basso G, Viola G.
Abstract : A small library of both [2,3-h] and [3,2-f] novel pyrroloquinolines equipped with an azolylmethyl group was designed and synthesized as nonsteroidal CYP19 aromatase inhibitors. The results showed that azolylmethyl derivatives 11, 13, 14, 21, and 22 exhibited an inhibitory potency on aromatase comparable to that of letrozole chosen as a reference compound. When assayed on CYP11B1 (steroid-11β-hydroxylase) and CYP17 (17α-hydroxy/17,20-lyase), compound 22 was found to be the best and most selective CYP19 inhibitor of them all. In a panel of nine human cancer cell lines, all compounds were either slightly cytotoxic or not at all. Docking simulations were carried out to inspect crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding, and heme iron coordination. This study, along with the prediction of the pharmacokinetics of compounds 11, 13, 14, 21, and 22, demonstrates that the pyrroloquinoline scaffold represents a starting point for the development of new pyrroloquinoline-based aromatase inhibitors.
|
Cytotoxicity against estrogen-dependent human MCF7 cells after 72 hrs by MTT assay
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Investigation of fluorinated and bifunctionalized 3-phenylchroman-4-one (isoflavanone) aromatase inhibitors.
Year : 2014
Volume : 22
Issue : 1
First Page : 126
Last Page : 134
Authors : Amato E, Bankemper T, Kidney R, Do T, Onate A, Thowfeik FS, Merino EJ, Paula S, Ma L.
Abstract : Fluorinated isoflavanones and bifunctionalized isoflavanones were synthesized through a one-step gold(I)-catalyzed annulation reaction. These compounds were evaluated for their in vitro inhibitory activities against aromatase in a fluorescence-based enzymatic assay. Selected compounds were tested for their anti-proliferative effects on human breast cancer cell line MCF-7. Compounds 6-methoxy-3-(pyridin-3-yl)chroman-4-one (3c) and 6-fluoro-3-(pyridin-3-yl)chroman-4-one (3e) were identified as the most potent aromatase inhibitors with IC₅₀ values of 2.5 μM and 0.8 μM. Therefore, these compounds have great potential for the development of pharmaceutical agents against breast cancer.
|
Inhibition of human recombinant aromatase expressed in baculovirus-infected cell system using 7-methoxy-trifluoromethylcoumarin as substrate after 30 mins by fluorescence assay
|
Homo sapiens
|
2.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Investigation of fluorinated and bifunctionalized 3-phenylchroman-4-one (isoflavanone) aromatase inhibitors.
Year : 2014
Volume : 22
Issue : 1
First Page : 126
Last Page : 134
Authors : Amato E, Bankemper T, Kidney R, Do T, Onate A, Thowfeik FS, Merino EJ, Paula S, Ma L.
Abstract : Fluorinated isoflavanones and bifunctionalized isoflavanones were synthesized through a one-step gold(I)-catalyzed annulation reaction. These compounds were evaluated for their in vitro inhibitory activities against aromatase in a fluorescence-based enzymatic assay. Selected compounds were tested for their anti-proliferative effects on human breast cancer cell line MCF-7. Compounds 6-methoxy-3-(pyridin-3-yl)chroman-4-one (3c) and 6-fluoro-3-(pyridin-3-yl)chroman-4-one (3e) were identified as the most potent aromatase inhibitors with IC₅₀ values of 2.5 μM and 0.8 μM. Therefore, these compounds have great potential for the development of pharmaceutical agents against breast cancer.
|
Cytotoxicity against human MCF7 cells after 24 to 96 hrs
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Investigation of fluorinated and bifunctionalized 3-phenylchroman-4-one (isoflavanone) aromatase inhibitors.
Year : 2014
Volume : 22
Issue : 1
First Page : 126
Last Page : 134
Authors : Amato E, Bankemper T, Kidney R, Do T, Onate A, Thowfeik FS, Merino EJ, Paula S, Ma L.
Abstract : Fluorinated isoflavanones and bifunctionalized isoflavanones were synthesized through a one-step gold(I)-catalyzed annulation reaction. These compounds were evaluated for their in vitro inhibitory activities against aromatase in a fluorescence-based enzymatic assay. Selected compounds were tested for their anti-proliferative effects on human breast cancer cell line MCF-7. Compounds 6-methoxy-3-(pyridin-3-yl)chroman-4-one (3c) and 6-fluoro-3-(pyridin-3-yl)chroman-4-one (3e) were identified as the most potent aromatase inhibitors with IC₅₀ values of 2.5 μM and 0.8 μM. Therefore, these compounds have great potential for the development of pharmaceutical agents against breast cancer.
|
Inhibition of human recombinant aromatase expressed in baculovirus infected insect cells using O-benzylfluorescein benzyl ester as substrate after 30 mins
|
Homo sapiens
|
1.1
nM
|
|
Journal : MedChemComm
Title : Flavans from Desmos cochinchinensis as potent aromatase inhibitors
Year : 2013
Volume : 4
Issue : 12
First Page : 1590
Last Page : 1596
Authors : Prachyawarakorn V, Sangpetsiripan S, Surawatanawong P, Mahidol C, Ruchirawat S, Kittakoop P
|
Inhibition of CYP11B1 (unknown origin) expressed in Chinese hamster V79MZ cells using [1,2-3H]-11-deoxycorticosterone as substrate at 500 nM preincubated for 60 mins followed by substrate addition measured after 25 mins by HPLC analysis relative to control
|
Homo sapiens
|
16.4
%
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
|
Inhibition of CYP11B2 (unknown origin) expressed in Chinese hamster V79MZ cells using [1,2-3H]-11-deoxycorticosterone as substrate at 500 nM preincubated for 60 mins followed by substrate addition measured after 50 mins by HPLC analysis relative to control
|
Homo sapiens
|
25.6
%
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
|
Inhibition of human CYP17 expressed in Escherichia coli using progesterone as substrate at 2 uM preincubated for 5 mins followed by enzyme addition measured after 30 mins by HPLC analysis relative to control
|
Homo sapiens
|
6.8
%
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
|
Inhibition of CYP19 isolated from microsomal fraction of human term placental tissue using [1beta-3H] androstenedione as substrate at 2 uM preincubated for 5 mins followed by enzyme addition measured after 20 mins by beta scintillation counting analysis relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
|
Inhibition of CYP19 isolated from microsomal fraction of human term placental tissue using [1beta-3H] androstenedione as substrate preincubated for 5 mins followed by enzyme addition measured after 20 mins by beta scintillation counting analysis
|
Homo sapiens
|
36.2
nM
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
|
Inhibition of human recombinant aromatase using 7-methoxy-trifluoromethylcoumarin as substrate assessed as formation of fluorescent metabolite after 30 mins by fluorescence assay
|
Homo sapiens
|
5.3
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities.
Year : 2015
Volume : 58
Issue : 6
First Page : 2623
Last Page : 2648
Authors : Lv W, Liu J, Skaar TC, Flockhart DA, Cushman M.
Abstract : Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer.
|
Inhibition of CYP19 (unknown origin) using O-benzyl fluorescein benzyl ester substrate preincubated for 10 mins by fluorimetric analysis relative to control
|
Homo sapiens
|
3.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors.
Year : 2015
Volume : 23
Issue : 13
First Page : 3472
Last Page : 3480
Authors : Pingaew R, Prachayasittikul V, Mandi P, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V.
Abstract : A series of 1,4-disubstituted-1,2,3-triazoles (13-35) containing sulfonamide moiety were synthesized and evaluated for their aromatase inhibitory effects. Most triazoles with open-chain sulfonamide showed significant aromatase inhibitory activity (IC50=1.3-9.4μM). Interestingly, the meta analog of triazole-benzene-sulfonamide (34) bearing 6,7-dimethoxy substituents on the isoquinoline ring displayed the most potent aromatase inhibitory activity (IC50=0.2μM) without affecting normal cell. Molecular docking of these triazoles against aromatase revealed that the compounds could snugly occupy the active site of the enzyme through hydrophobic, π-π stacking, and hydrogen bonding interactions. The potent compound 34 was able to form hydrogen bonds with Met374 and Ser478 which were suggested to be the essential residues for the promising inhibition. The study provides compound 34 as a potential lead molecule of anti-aromatase agent for further development.
|
Inhibition of aromatase (unknown origin) expressed in JEG-3 cells
|
Homo sapiens
|
0.89
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health.
Year : 2015
Volume : 58
Issue : 19
First Page : 7634
Last Page : 7658
Authors : Thomas MP, Potter BV.
Abstract : In 1994, following work from this laboratory, it was reported that estrone-3-O-sulfamate irreversibly inhibits a new potential hormone-dependent cancer target steroid sulfatase (STS). Subsequent drug discovery projects were initiated to develop the core aryl O-sulfamate pharmacophore that, over some 20 years, have led to steroidal and nonsteroidal drugs in numerous preclinical and clinical trials, with promising results in oncology and women's health, including endometriosis. Drugs have been designed to inhibit STS, e.g., Irosustat, as innovative dual-targeting aromatase-steroid sulfatase inhibitors (DASIs) and as multitargeting agents for hormone-independent tumors, such as the steroidal STX140 and nonsteroidal counterparts, acting inter alia through microtubule disruption. The aryl sulfamate pharmacophore is highly versatile, operating via three distinct mechanisms of action, and imbues attractive pharmaceutical properties. This Perspective gives a personal view of the work leading both to the therapeutic concepts and these drugs, their current status, and how they might develop in the future.
|
Inhibition of recombinant human aromatase using 7-methoxy-4-trifluoromethyl coumarin as substrate measured at anoxic conditions by fluorescence analysis
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological characterization of 3-(imidazol-1-ylmethyl)piperidine sulfonamides as aromatase inhibitors.
Year : 2016
Volume : 26
Issue : 13
First Page : 3192
Last Page : 3194
Authors : Di Matteo M, Ammazzalorso A, Andreoli F, Caffa I, De Filippis B, Fantacuzzi M, Giampietro L, Maccallini C, Nencioni A, Parenti MD, Soncini D, Del Rio A, Amoroso R.
Abstract : The most frequently used treatment for hormone receptor positive breast cancer in post-menopausal women are aromatase inhibitors. In order to develop new aromatase inhibitors, we designed and synthesized new imidazolylmethylpiperidine sulfonamides using the structure of the previously identified aromatase inhibitor SYN 20028567 as starting lead. By this approach, three new aromatase inhibitors with IC50 values that are similar to that of letrozole and SYN 20028567 were identified.
|
Inhibition of recombinant human CYP19 expressed in baculovirus infected insect cells using MFC as substrate measured after 30 mins by fluorometric analysis
|
Homo sapiens
|
5.3
nM
|
|
Journal : Bioorg Med Chem
Title : A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β.
Year : 2016
Volume : 24
Issue : 21
First Page : 5400
Last Page : 5409
Authors : Zhao LM, Jin HS, Liu J, Skaar TC, Ipe J, Lv W, Flockhart DA, Cushman M.
Abstract : The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) derivatives with dual aromatase inhibitory activity and estrogen receptor binding activity. In the present study, some of the structural features of the potent AI letrozole were incorporated into the lead compound (norendoxifen) to afford a series of new dual AI/SERM agents based on a symmetrical diphenylmethylene substructure that eliminates the problem of E,Z isomerization encountered with norendoxifen-based AI/SERMs. Compound 12d had good aromatase inhibitory activity (IC50=62.2nM) while also exhibiting good binding activity to both ER-α (EC50=72.1nM) and ER-β (EC50=70.8nM). In addition, a new synthesis was devised for the preparation of norendoxifen and its analogues through a bis-Suzuki coupling strategy.
|
Inhibition of aromatase activity in human T47D cells at 100 uL after 24 hrs
|
Homo sapiens
|
58.0
%
|
|
Journal : Eur J Med Chem
Title : Analogue based drug design, synthesis, molecular docking and anticancer evaluation of novel chromene sulfonamide hybrids as aromatase inhibitors and apoptosis enhancers.
Year : 2016
Volume : 124
First Page : 946
Last Page : 958
Authors : Ghorab MM, Alsaid MS, Al-Ansary GH, Abdel-Latif GA, Abou El Ella DA.
Abstract : Twenty novel chromene derivatives carrying different sulfonamide moieties (3-22) were designed and synthesized. All the newly prepared compounds were evaluated for their in vitro anticancer activity against breast cancer cell line (T47D). Most of the synthesized compounds showed good to moderate activity (IC50 = 8.8-108.9 μM), where compound 16 (IC50 = 8.8 μM) exhibited higher activity compared to doxorubicin (IC50 = 9.8 μM). In order to determine the mechanism of the anticancer activity in T47D cells, the effect of the most potent compounds (5-8, 11-14, and 16-18) on the aromatase activity was tested. Most of the selected compounds showed significant inhibitory effect on the aromatase activity, with compound 18 showing IC50 = 4.66 μM. Furthermore, apoptosis studies were conducted on two of the most potent compounds (8 & 16) to estimate the proapoptotic potential of our compounds. Both induced the levels of active caspase 3, caspase 8 and caspase 9. Moreover, they surprisingly boosted the Bax/Bcl2 ratio 5936 & 33,000 folds, respectively compared to the control. Moreover, they showed mild cytotoxic effect (IC50 = 183.8 μM & 172.04 μM, respectively) in normal breast cells 184A1. Finally, a molecular docking study was performed to investigate the probable interaction with the aromatase enzyme.
|
Inhibition of aromatase activity in human T47D cells after 24 hrs
|
Homo sapiens
|
58.0
%
|
|
Journal : Eur J Med Chem
Title : Aromatase inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and molecular modeling studies of novel phenothiazine derivatives carrying sulfonamide moiety as hybrid molecules.
Year : 2017
Volume : 134
First Page : 304
Last Page : 315
Authors : Ghorab MM, Alsaid MS, Samir N, Abdel-Latif GA, Soliman AM, Ragab FA, Abou El Ella DA.
Abstract : Hybrid molecules are used as anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5-22, 24 and 25 of promising anticancer activity. Compounds 11 and 13 revealed more potent anticancer properties (IC50 8.1 and 8.8 μM) than that of the reference drug (doxorubicin, IC50 = 9.8 μM) against human breast cancer cell line (T47D). To determine the mechanism of their anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect. The study results disclose that the most potent aromatase inhibitors 11 and 13 showed the lowest IC50 (5.67 μM and 6.7 μM), respectively on the target enzyme. Accordingly, the apoptotic effect of the most potent compound 11 was extensively investigated and showed a marked increase in Bax level up to 55,000 folds, and down-regulation in Bcl2 to 5.24*10-4 folds, in comparison to the control. Furthermore, the effect of compound 11 on caspases 3, 8 and 9 was evaluated and was found to increase their levels by 20, 34, and 8.9 folds, respectively, which indicates the activation of both intrinsic and extrinsic pathways. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking and computer aided ADMET studies were adopted to confirm their mechanism of action.
|
Inhibition of aromatase (unknown origin) using O-benzyl fluorescein benzyl ester as substrate in presence of NADPH-generating system by fluorescence assay
|
Homo sapiens
|
1.9
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, molecular docking, and QSAR study of sulfonamide-based indoles as aromatase inhibitors.
Year : 2018
Volume : 143
First Page : 1604
Last Page : 1615
Authors : Pingaew R, Mandi P, Prachayasittikul V, Prachayasittikul S, Ruchirawat S, Prachayasittikul V.
Abstract : Thirty four of indoles bearing sulfonamides (11-44) were synthesized and evaluated for their anti-aromatase activities. Interestingly, all indole derivatives inhibited the aromatase with IC50 range of 0.7-15.3 μM. Indoles (27-36) exerted higher aromatase inhibitory activity than that of ketoconazole. The phenoxy analogs 28 and 34 with methoxy group were shown to be the most potent compounds with sub-micromolar IC50 values (i.e., 0.7 and 0.8 μM, respectively) without affecting to the normal cell line. Molecular docking demonstrated that the indoles 28, 30 and 34 could occupy the same binding site on the aromatase pocket and share several binding residues with those of the natural substrate (androstenedione), which suggested the competitive binding could be the mode of inhibition of the compounds. The most potent analog 28 could mimic H-bond interactions of the natural androstenedione with MET374 and ASP309 residues on the aromatase. QSAR model also revealed that the para-phenoxy indole (28) affords the higher value of electronegativity descriptor MATS6e as well as the higher inhibitory activity compared with that of the ortho-phenoxy compound (34). The study highlighted a series of promising indoles to be potentially developed as novel aromatase inhibitors for therapeutics.
|
Inhibition of human aromatase using androstenedione as substrate and NADPH preincubated for 24 hrs followed by substrate addition measured after 24 hrs by ELISA
|
Homo sapiens
|
49.5
nM
|
|
Journal : Eur J Med Chem
Title : Potent aromatase inhibitors and molecular mechanism of inhibitory action.
Year : 2018
Volume : 143
First Page : 426
Last Page : 437
Authors : Kang H, Xiao X, Huang C, Yuan Y, Tang D, Dai X, Zeng X.
Abstract : Estrogen is a significant factor in the maintenance and progression of hormone-dependent breast cancer. As well known, aromatase mediates the production of estrogen. Thus, inhibition of aromatase with chemical molecules has been considered to be an effective treatment for estrogen receptor-positive (ER+) breast cancer. In this work, we designed and synthesized a series of novel non-steroidal molecules containing 2-phenylindole scaffold and moiety of either imidazole or 1,2,4-triazole to enhance their binding capacity with the aromatase. Among these molecules, a compound named as 8o was confirmed experimentally to have the highest inhibitory activity to aromatase. Further cell activity assay proved that compound 8o has low cytotoxicity and is a promising lead for developing novel aromatase inhibitors. Molecular modeling and simulation techniques were performed to identify the binding modes of letrozole and 8o with the aromatase. Analysis of energy of the two compound-aromatase complexes revealed that the 8o has low binding energy (strong binding affinity) to the aromatase as compared to letrozole, which was in accordance with the experimental results. As concluded, a combination of experimental and computational approaches facilitates us to understand the molecular mechanism of inhibitory action and discover more potent non-steroidal AIs against aromatase, thereby opening up a novel therapeutic strategy for hormone-dependent breast cancer.
|
Inhibition of CYP19A1 (unknown origin) preincubated with NADPH followed by DBF substrate addition after 30 mins by fluorescence based assay
|
Homo sapiens
|
9.95
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1.
Year : 2017
Volume : 27
Issue : 24
First Page : 5393
Last Page : 5399
Authors : Prior AM, Yu X, Park EJ, Kondratyuk TP, Lin Y, Pezzuto JM, Sun D.
Abstract : In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3'-nitrogen coordinating with the heme group.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
12.65
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-0.32
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
9.79
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
8.9
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
22.09
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
2.89
%
|
|
|
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
|
-8.63
%
|
|
|
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
|
-11.02
%
|
|
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 aromatase in human MCF-7aro cells using [1beta-3H] androstenedione as substrate incubated for 1 hr by liquid scintillation counting method
|
Homo sapiens
|
1.9
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, biological evaluation, and docking study of indole aryl sulfonamides as aromatase inhibitors.
Year : 2020
Volume : 185
First Page : 111815
Last Page : 111815
Authors : Fantacuzzi M, De Filippis B, Gallorini M, Ammazzalorso A, Giampietro L, Maccallini C, Aturki Z, Donati E, Ibrahim RS, Shawky E, Cataldi A, Amoroso R.
Abstract : In order to identify new aromatase enzyme inhibitors, thirty aryl sulfonamide derivatives containing an indole nucleus have been synthesized. The enzyme inhibition assay showed that four compounds inhibit aromatase in the sub-micromolar range. Loading concentrations of these four compounds were afterwards tested for cell viability and cytotoxicity on MCF7 human breast cancer cells, revealing a time- and dose-dependent decrease of active metabolizing cells over the time of the culture (0-72 h), starting from a concentration of 100 μM. Likewise LDH released raised up to 40% at early time of exposures (24 h). Finally, the docking study showed that the best active compounds efficiently bound in the active site of the aromatase; high values of HBD and low levels of HBA are the principal requirement evidenced by the QSAR model.
|
Inhibition of recombinant human aromatase expressed in baculovirus infected insect cells using O-benzyl fluorescein benzyl ester as substrate in presence of NADPH generating system by fluorescence based analysis
|
Homo sapiens
|
1.9
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis, molecular docking, and QSAR study of bis-sulfonamide derivatives as potential aromatase inhibitors.
Year : 2019
Volume : 27
Issue : 19
First Page : 115040
Last Page : 115040
Authors : Leechaisit R, Pingaew R, Prachayasittikul V, Worachartcheewan A, Prachayasittikul S, Ruchirawat S, Prachayasittikul V.
Abstract : A library of bis-sulfonamides (9-26) were synthesized and tested for their aromatase inhibitory activities. Interestingly, all bis-sulfonamide derivatives inhibited the aromatase with IC<sub>50</sub> range of 0.05-11.6 μM except for compound 23. The analogs 15 and 16 bearing hydrophobic chloro and bromo groups exhibited the potent aromatase inhibitory activity in sub-micromolar IC<sub>50</sub> values (i.e., 50 and 60 nM, respectively) with high safety index. Molecular docking revealed that the chloro and bromo benzenesulfonamides (15 and 16) may play role in the hydrophobic interaction with Leu477 of the aromatase to mimic steroidal backbone of the natural substrate, androstenedione. QSAR study also revealed that the most potent activity of compounds was governed by van der Waals volume (GATS6v) and mass (Mor03m) descriptors. Finally, the two compounds (15 and 16) were highlighted as promising compounds to be further developed as novel aromatase inhibitors.
|
Inhibition of recombinant human aromatase preincubated for 10 mins followed by substrate and beta-NADP+ addition and measured for 60 mins by fluorescence method
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Rational design of allosteric modulators of the aromatase enzyme: An unprecedented therapeutic strategy to fight breast cancer.
Year : 2019
Volume : 168
First Page : 253
Last Page : 262
Authors : Spinello A, Martini S, Berti F, Pennati M, Pavlin M, Sgrignani J, Grazioso G, Colombo G, Zaffaroni N, Magistrato A.
Abstract : Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern. Serendipitous findings indicate that aromatase may be non-competitively inhibited by clinically employed drugs and/or industrial chemicals. Here, by performing in silico screening on two putative allosteric sites, molecular dynamics and free energy simulations, supported by enzymatic and cell-based assays, we identified five leads inhibiting the enzyme via a non-active site-directed mechanism. This study provides new compelling evidences for the existence of an allosteric regulation of aromatase and for the possibility of exploiting it to modulate estrogens biosynthesis. Such modulation can aptly reduce side effects caused by the complete estrogen deprivation therapy, and, possibly, delay/avoid the onset of resistance.
|
Inhibition of recombinant human aromatase at 1 uM preincubated for 10 mins followed by substrate and beta-NADP+ addition and measured for 60 mins by fluorescence method
|
Homo sapiens
|
91.0
%
|
|
Journal : Eur J Med Chem
Title : Rational design of allosteric modulators of the aromatase enzyme: An unprecedented therapeutic strategy to fight breast cancer.
Year : 2019
Volume : 168
First Page : 253
Last Page : 262
Authors : Spinello A, Martini S, Berti F, Pennati M, Pavlin M, Sgrignani J, Grazioso G, Colombo G, Zaffaroni N, Magistrato A.
Abstract : Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern. Serendipitous findings indicate that aromatase may be non-competitively inhibited by clinically employed drugs and/or industrial chemicals. Here, by performing in silico screening on two putative allosteric sites, molecular dynamics and free energy simulations, supported by enzymatic and cell-based assays, we identified five leads inhibiting the enzyme via a non-active site-directed mechanism. This study provides new compelling evidences for the existence of an allosteric regulation of aromatase and for the possibility of exploiting it to modulate estrogens biosynthesis. Such modulation can aptly reduce side effects caused by the complete estrogen deprivation therapy, and, possibly, delay/avoid the onset of resistance.
|
Inhibition of recombinant human aromatase using 7-methoxy-trifluoromethylcoumarin as substrate incubated for 30 mins by fluorescence microplate reader analysis
|
Homo sapiens
|
2.18
nM
|
|
Inhibition of recombinant human aromatase using 7-methoxy-trifluoromethylcoumarin as substrate incubated for 30 mins by fluorescence microplate reader analysis
|
Homo sapiens
|
2.178
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and aromatase inhibitory evaluation of 4-N-nitrophenyl substituted amino-4H-1,2,4-triazole derivatives.
Year : 2016
Volume : 24
Issue : 19
First Page : 4723
Last Page : 4730
Authors : Song Z, Liu Y, Dai Z, Liu W, Zhao K, Zhang T, Hu Y, Zhang X, Dai Y.
Abstract : In this paper, 13 4-N-nitrophenyl substituted amino-4H-1,2,4-triazole derivatives were synthesized and their aromatase inhibitory activities were measured. The results show that the substitution of the groups on benzyl group can further improve their bioactivity and the compound with Cl on the para position of benzyl has the highest bioactivity (IC50=9.02nM). A QSAR model was constructed from the 13 compounds with genetic function approximation using DS 2.1 package. This model can explain 90.09% of the variance (R(2)Adj), while it can predict 84.95% of the variance (R(2)cv) with the confidence interval of 95%.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-10.8
%
|
|
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
|
-0.08
%
|
|
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
|
-0.08
%
|
|
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 human aromatase using ASD as substrate incubated for 16 hrs by UV/vis-spectrophotometry
|
Homo sapiens
|
10.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors.
Year : 2020
Volume : 11
Issue : 5
First Page : 732
Last Page : 739
Authors : Caciolla J, Spinello A, Martini S, Bisi A, Zaffaroni N, Gobbi S, Magistrato A.
Abstract : Breast cancer (BC) is the most diffused cancer type in women and the second leading cause of death among the female population. Effective strategies to fight estrogen responsive (ER+) BC, which represents 70% of all BC cases, rely on estrogen deprivation, via the inhibition of the aromatase enzyme, or the modulation of its cognate estrogen receptor. Current clinical therapies significantly increased patient survival time. Nevertheless, the onset of resistance in metastatic BC patients undergoing prolonged treatments is becoming a current clinical challenge, urgently demanding to devise innovative strategies. In this context, here we designed, synthesized, and performed in vitro inhibitory tests on the aromatase enzyme and distinct ER+/ER- BC cell line types of novel azole bridged xanthones. These compounds are active in the low μM range and behave as dual-mode inhibitors, targeting both the orthosteric and the allosteric sites of the enzyme placed along one access channel. Classical and quantum-classical molecular dynamics simulations of the new compounds, as compared with selected steroidal and nonsteroidal inhibitors, provide a rationale to the observed inhibitory potency and supply the guidelines to boost the activity of inhibitors able to exploit coordination to iron and occupation of the access channel to modulate estrogen production.
|
Inhibition of human aromatase assessed as reduction in fluorescence intensity using 7-methoxy-4-trifluoromethyl coumarin as a substrate at 1 uM by fluorimetric assay relative to control
|
Homo sapiens
|
100.0
%
|
|
|
Inhibition of aromatase (unknown origin)
|
Homo sapiens
|
1.0
nM
|
|
|
Inhibition of human aromatase assessed as reduction in fluorescence intensity preincubated with NADPH regenerating system for 10 mins followed by substrate addition incubated for 60 mins by fluorescence based microplate reader analysis
|
Homo sapiens
|
4.0
nM
|
|
