Spironolactone-related inhibitors of type II 17 beta-hydroxysteroid dehydrogenase: Chemical synthesis, receptor binding affinities, and proliferativeantiproliferative activities

The family of 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) catalyze s the formation and inactivation of testosterone (T), dihydrotestosterone ( DHT), and estradiol (E-2), thus playing a crucial role in the regulation of active steroid hormones in target tissues. Among the five known 17 beta-HS D enzymes, type II catalyzes the oxidation of E-2 into estrone (El), T into androstenedione, DHT into androstanedione, and 20 alpha-dihydroprogesteron e into progesterone. Specific inhibitors are thus an interesting means to s tudy the regulation and to probe the structure of type II 17 beta-HSD. In t his context, we have efficiently synthesized a series of 7 alpha-thioalkyl and 7 alpha-thioaryl derivatives of spironolactone that inhibit type II 17 beta-HSD. These new C19-steroidal inhibitors possess two important pharmaco phores, namely 17-spiro-gamma-lactone and a bulky side-chain at the 7 alpha -position. It was found that a para-substituted benzylthio group at the 7 a lpha-position enhances the inhibitory potency of spironolactone derivatives on type II 17 beta-HSD. In fact, the compound with a para-hydroxy-benzylth io group showed an IC50 value of 0.5 mu M against type II 17 beta-HSD, wher eas the compound with a para-[2-(1-piperidinyl)-ethoxy]-benzylthio group in hibited this enzyme with an IC50 value of 0.7 mu M. The latter inhibitor is more selective than the former because it did not show any inhibitory pote ncy against P450 aromatase as well as any affinity towards four steroid rec eptors (AR, PR, GR, ER). As a result, this inhibitor did not show any proli ferative effect on androgen-sensitive Shionogi cells and estrogen-sensitive ZR-75-1 cells. These findings contribute to a better knowledge of the stru cture of type II 17 beta-HSD and offer an interesting tool to study the reg ulation of this enzyme in several biological systems. (C) 1999 Elsevier Sci ence Ltd. All rights reserved.