Design, chemical synthesis and biological evaluation of 3-spiromorpholinone/3-spirocarbamate androsterone derivatives as inhibitors of 17 beta-hydroxysteroid dehydrogenase type 3

作者：Djigoue Guy Bertrand; Kenmogne Lucie Carolle; Roy Jenny; Maltais Rene; Poirier Donald^*

来源：Bioorganic & Medicinal Chemistry, 2015, 23(17): 5433-5451.

DOI：10.1016/j.bmc.2015.07.049

• Enzyme inhibitor
• Androgen
• Spiromorpholinone
• Chemical synthesis
• Prostate cancer
• 17 beta-Hydroxysteroid dehydrogenase

17 beta-Hydroxysteroid dehydrogenase type 3 (17 beta-HSD3) is a key enzyme involved in the biosynthesis of testosterone and dihydrotestosterone. These hormones are known to stimulate androgen-dependent prostate cancer. In order to generate effective inhibitors of androgen biosynthesis without androgenic effect, we synthesized a new family of 3-spiromorpholinone and 3-spirocarbamate androsterone derivatives bearing diversified hydrophobic groups. We also tested their inhibitory activity in a microsomal fraction of 17 beta-HSD3-containing rat testes, and their androgenic effect on androgen-sensitive LAPC-4 cells. From our first structure-activity relationship (SAR) study, we noted that compound 7e inhibited 17 beta-HSD3 (77% at 0.1 mu M) compared to our reference compound RM-532-105 (76% at 0.1 mu M), but exhibited a residual androgenic effect. A library of 7e analogue compounds was next synthesized in order to generate compounds with reduced androgenic activity. In this new SAR study, the sulfonamide compound 7e21 and the carboxamide compound 7e22 inhibited 17 beta-HSD3 (IC50 = 28 and 88 nM, respectively). These two compounds were not androgenic and not cytotoxic even at the highest concentration tested, but their inhibitory activity decreased in intact LNCaP cells overexpressing 17 beta-HSD3 (LNCaP[17 beta-HSD3]). Structural modifications of these two lead compounds could however be tested to produce a second generation of 17 beta-HSD3 inhibitors.

• 出版日期2015-9-1