👤 Francisco Cortés-Benítez

Prostate cancer is the most common cancer among men and the development of new therapeutic agents is needed for its treatment and/or diagnosis. 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is involved in the production of androgens, which stimulates the proliferation of prostate cancer cells. Piperazinomethyl-androsterone sulfonamide derivatives were developed as 17β-HSD3 inhibitors and the concentration of a representative sulfonamide derivative (compound 1) was found to accumulate in prostate tumor tissues relatively to plasma in a mouse xenograft experiment. This finding gives us the opportunity to specifically target the prostate cancer tumors through the development of a radiolabelled version of compound 1 toward targeted molecular radiotherapy or radioimaging diagnosis. The chemical synthesis of fluorinated and iodinated analogs of compound 1 was achieved, leading to a series of compounds with similar levels of inhibition as the initial candidate. From 17β-HSD3 inhibition activity, molecular modeling and mouse plasma-concentration studies, the most promising compound of this series was selected, its Show less

A new androsterone derivative bearing a 16β-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 17β-HSD3 using microsomal fraction of rat testes as well as transfected LNCaP[17β-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 17β-HSD3 inhibitory activity in the microsomal fraction of rat testes, but not in whole LNCaP[17β-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 17β-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 RM-532-105 (1) and FCO-586-119 (5) can compete for the cofactor-binding site displaying better binding energy than NADP Show less

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a major player in human endocrinology, being one of the most important enzymes involved in testosterone production. To capitalize on the discovery of RM-532-105, a steroidal 17β-HSD3 inhibitor, we explored the effect of its backbone configuration on inhibitory activity, androgenic profile, and metabolic stability. Two modifications that greatly alter the natural shape of steroids, i.e. inversion of the methyl on carbon 13 (13α-CH Show less