title: 1-[(Benzofuran-2-yl)phenylmethyl]triazoles as steroidogenic inhibitors: synthesis and in vitro inhibition of human placental CYP19 aromatase.
abstract: Hormone-dependent breast cancer is stimulated by the female hormones oestrone and oestradiol, therefore compounds which inhibit the specific enzymes involved in the formation of the nitogenic hormones, namely CYP19 aromatase (P450arom) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 1, are targets of therapeutic interest for the treatment of breast cancer. A series of novel 1-[(benzofuran-2-yl)phenylmethyl]1,2,4-triazoles were prepared using a three-step synthesis and evaluated for their inhibitory activity against human placental aromatase in vitro, using [1,2,6,7-3H]androstenedione as the substrate for the aromatase enzyme. Inhibitory activity was dependent on both substituent and position of substitution, with introduction of small electron-withdrawing groups in the phenyl ring showing optimum activity (IC50 ranging from 0.065 to 2.02 microm). Substitution in the benzofuran ring resulted in a loss of activity when substituted at C-5 (IC50 > 20 microm). The compounds were all shown to exhibit weak inhibitory activity against rat testes P450 17 (17,20-lyase), indicating good selectivity towards P450arom.
authors.affiliation: Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, UK.
authors.forename: T K
authors.initials: TK
authors.lastname: Vinh
authors.forename: S W
authors.initials: SW
authors.lastname: Yee
authors.forename: A J
authors.initials: AJ
authors.lastname: Kirby
authors.forename: P J
authors.initials: PJ
authors.lastname: Nicholls
authors.forename: C
authors.initials: C
authors.lastname: Simons
mesh_terms: D000328:Adult; D000818:Animals; D047072:Aromatase Inhibitors; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004967:Estrogens / Q000096:biosynthesis; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008861:Microsomes / Q000201:enzymology; D010920:Placenta / Q000187:drug effects / Q000201:enzymology*; D011247:Pregnancy; D051381:Rats; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013256:Steroids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D013737:Testis / Q000187:drug effects / Q000201:enzymology; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D001572:Benzofurans; D004791:Enzyme Inhibitors; D004967:Estrogens; D007202:Indicators and Reagents; D013256:Steroids; D014230:Triazoles; D013254:Steroid 17-alpha-Hydroxylase