Author/Editor | Starčević, Štefan; Brožič, Petra; Turk, Samo; Cesar, Jožko; Lanišnik-Rižner, Tea; Gobec, Stanislav | |
Title | Synthesis and biological evaluation of (6- and 7-phenyl) coumarin derivatives as selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 | |
Type | članek | |
Source | J Med Chem | |
Vol. and No. | Letnik 54, št. 1 | |
Publication year | 2011 | |
Volume | str. 248-61 | |
Language | eng | |
Abstract | 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is an enzyme that catalyzes NADPH-dependent reduction of the weak estrogen, estrone, into the most potent estrogen, estradiol, which exerts proliferative effects via the estrogen receptors. Overexpression of 17beta-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis; thus, 17beta-HSD1 represents an attractive target for the development of new therapies. We have discovered that simple coumarines 1 and 2 significantly inhibit 17beta-HSD1 in a recombinant enzyme assay, with high selectivity against 17beta-HSD2. We postulated that the introduction of various p-substituted phenyl moieties to position 6 or 7 of the coumarin core using the Suzuki-Miyaura cross-coupling reaction would provide mimetics of steroidal structures with improved inhibition of 17beta-HSD1. The best inhibitor in the series proved to be 6a, with an IC(50) of 270 nM, and with exceptional selectivity for 17beta-HSD1 over 17beta-HSD2 and against the alpha and beta estrogen receptors. | |
Descriptors | 17-HYDROXYSTEROID DEHYDROGENASES COUMARINS ESTROGENS NADH DEHYDROGENASE ESTRADIOL RECEPTORS, ESTROGEN BIOLOGICAL ASSAY |