Androsterone derivatives substituted at position 16: chemical synthesis, inhibition of type 3 17beta-hydroxysteroid dehydrogenase, binding affinity for steroid receptors and proliferative/antiproliferative activity on Shionogi (AR+) cells.

A series of androsterone (ADT) derivatives substituted at position 16 were efficiently synthesized in short reaction sequences; the ether analogues were also synthesized in the case of the methyl and allyl derivatives. The aim of this study was to develop inhibitors of the steroidogenic enzyme type 3 17beta-hydroxysteroid dehydrogenase and then evaluate their ability to inhibit this activity in transfected HEK-293 cells. For each compound we measured the percentage of inhibition of the transformation of 4-androstene-3,17-dione, the natural substrate of this steroidogenic enzyme, into the active androgen testosterone. The synthesized compounds proved to be weak inhibitors of this enzyme, but interestingly, these ADT derivatives do not bind to androgen, estrogen, glucocorticoid, and progestin receptors, suggesting no unsuitable receptor-mediated effects. One exception, 16alpha-(3'-bromopropyl)-5alpha-androstane-3alpha,17beta-diol, the only compound bearing a hydroxy group at position 17beta instead of a ketone, showed a strong binding affinity for the androgen receptor (70% at 1 microM) and also exhibited an antiproliferative activity on Shionogi (AR+) cells (86% at 1 microM), which was comparable to that of hydroxyflutamide, a pure antiandrogen (100% at 1 microM).