Inhibitors of type II 17 beta-hydroxysteroid dehydrogenase

The 17 beta -hydroxysteroid dehydrogenases (17 beta -HSDs) are involved in the last step of the biosynthesis of sex steroids from cholesterol. This fa mily of steroidogenic enzymes constitutes an interesting target in the cont rol of the concentration of estrogens and androgens. Among the isoforms of 17 beta -HSD, type II preferentially catalyzes the oxidation of estradiol ( E-2), testosterone (T), dihydrotestosterone (DHT), and 20 alpha -dihydropro gesterone (20 alpha -DHP). Based on structure-activity relationship studies , we have developed steroidal spirolactones as inhibitors of type II 17 bet a -HSD using different steroid nuclei: a C18-steroid (lactones 1 and 10), a n antiestrogenic nucleus (lactone 2), and a C19-steroid (lactone 28). We kn ow these inhibitors are selective for type II 17 beta -HSD as no or only we ak inhibition was observed for types I and III. They also have no prolifera tive (androgenic) activity on androgen sensitive (AR(+)) Shionogi cells whe reas their proliferative (estrogenic) activity on estrogen sensitive (ER+) ZR-75-1 cells depends on the nature of the steroid nucleus. Lactones 1 and 10 are weak estrogens, while lactones 2 and 28 do not exert estrogenic acti vity, in fact lactone 2 is an antiestrogen. Lactones 1, 2, 10 and 28 were a lso tested in an identical assay with a series of enzyme substrates, C19-st eroid diols, and known inhibitors, for the oxidation of testosterone and es tradiol into androstenedione and estrone, respectively. From this comparati ve study, the best inhibitors of type II 17 beta -HSD (oxidase activity) we re identified, but none of them were clearly more potent than the hydroxyla ted (reduced) forms of enzyme substrates, E-2, T, and DHT. Such inhibitors remain, however, useful tools to, (1) further elucidate the role of type II 17 beta -HSD. and (2) regulate the level of active estrogens, androgens an d progesterone. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.