ABSTRACT
A series of 4-aryl substituted 7-hydroxy-flavones were prepared using the three-step Baker-Venkataraman synthesis in good overall yields. The flavones were all evaluated in vitro for inhibitory activity against aromatase (P450AROM, CYP19), using human placental microsomes, and for inhibitory activity against 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD-1) using human placental cytosol. The phenyl, 4-fluoro-phenyl and 4-bromo-phenyl derivatives displayed moderate inhibitory activity against P450AROM (IC50 17.2, 13.5 and 10.1 microM, respectively), none of the flavones, including the standard genistein, displayed any inhibitory activity against 17beta-HSD type 1 at 100 microM concentration.
Subject(s)
Estrogen Antagonists/pharmacology , Estrone/antagonists & inhibitors , Flavonoids/pharmacology , 17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Aromatase Inhibitors , Cytosol/enzymology , Drug Evaluation, Preclinical , Estradiol/biosynthesis , Estrogen Antagonists/chemistry , Estrone/biosynthesis , Female , Flavonoids/chemical synthesis , Flavonoids/chemistry , Humans , Inhibitory Concentration 50 , Microsomes/enzymology , PlacentaABSTRACT
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.
Subject(s)
Aromatase Inhibitors , Benzofurans/chemical synthesis , Benzofurans/pharmacology , Enzyme Inhibitors/pharmacology , Placenta/enzymology , Steroids/antagonists & inhibitors , Steroids/biosynthesis , Triazoles/chemical synthesis , Triazoles/pharmacology , Adult , Animals , Chromatography, High Pressure Liquid , Estrogens/biosynthesis , Female , Humans , In Vitro Techniques , Indicators and Reagents , Magnetic Resonance Spectroscopy , Male , Microsomes/enzymology , Placenta/drug effects , Pregnancy , Rats , Steroid 17-alpha-Hydroxylase/metabolism , Structure-Activity Relationship , Testis/drug effects , Testis/enzymologyABSTRACT
The synthesis of a series of novel 1-[(benzofuran-2-yl)phenylmethyl]-triazoles and -tetrazoles is described. The compounds were tested for human placental aromatase inhibition in vitro, using [1beta-3H]-androstenedione as the substrate for the aromatase enzyme, the percentage inhibition and IC50 data is included.
