16-Picolyl-androsterone derivative exhibits potent 17β-HSD3 inhibitory activity, improved metabolic stability and cytotoxic effect on various cancer cells: Synthesis, homology modeling and docking studies

A new androsterone derivative bearing a 16 beta-picolyl group (compound 5; FCO-586-119) was synthetized in four steps from the lead compound 1 (RM-532-105). We measured its inhibitory activity on 17 beta-HSD3 using microsomal fraction of rat testes as well as transfected LNCaP[17 beta-HSD3] cells. We then assessed its metabolic stability as well as its cytotoxic effect against a panel of cancer cell lines. The addition of a picolyl moiety at C-16 of RM-532-105 steroid core improves the 17 beta-HSD3 inhibitory activity in the microsomal fraction of rat testes, but not in whole LNCaP[17 beta-HSD3] cells. Interestingly, this structural modification enhances 3-fold the metabolic stability in conjunction with a significant cytotoxic effect against pancreatic, ovarian, breast, lung, and prostate cancer cells. Because the inhibitory activity data against 17 beta-HSD3 suggested that both steroid derivatives are non-competitive inhibitors, we performed docking and molecular dynamics simulations using a homology model of this membrane-associated enzyme. The results of these simulations revealed that both RM532-105 (1) and FCO-586-119 (5) can compete for the cofactor-binding site displaying better binding energy than NADP+.

Automated summary

The new synthesized androsterone derivative showed improved inhibitory activity in rat testes microsomal fraction but not in whole cells. Additionally, structural modification increased metabolic stability and demonstrated significant cytotoxicity against various cancer cell lines. Furthermore, both the lead compound and the derivative showed better binding energy than NADP+ at the cofactor-binding site according to molecular dynamics simulations.