Synthesis and Biological Evaluation of (6-and 7-Phenyl) Coumarin Derivatives as Selective Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1

17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-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 17 beta-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis, thus, 17 beta-HSD1 represents an attractive target for the development of new therapies We have discovered that simple coumarines 1 and 2 significantly inhibit 17 beta-HSD1 in a recombinant enzyme assay, win h high selectivity against 17 beta-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 17 beta-HSD1 The best inhibitor in the series proved to be 6a, with an IC50 of 270 nM, and with exceptional selectivity for 17 beta-HSD1 over 17 beta-HSD2 and against the alpha and beta estrogen receptors