New steroidal lactones as 5α-reductase inhibitors and antagonists for the androgen receptor

This study reports the synthesis of several new steroidal lactones: 5α,6β-dibromo-17a-oxa-d-homoandrostane-3β-yl-3′-oxapentanoate (11), 5α,6β-dibromo-17a-oxa-d-homoandrostane-3β-yl-propanoate (12), 5α,6β-dibromo-17a-oxa-d-homoandrostane-3β-yl-butanoate (13), 5α,6β-dibromo-17a-oxa-d-homoandrostane-3β-yl-pentanoate (14), 5α,6β-dibromo-17a-oxa-d-homoandrostane-3β-yl-hexanoate (15), 17a-oxa-d-homoandrost-5-en-17-one-3β-yl-3′-oxapentanoate (16), 17a-oxa-d-homoandrost-5-en-17-one-3β-yl-propanoate (17), 17a-oxa-d-homoandrost-5-en-17-one-3β-yl-butanoate (18), 17a-oxa-d-homoandrost-5-en-17-one-3β-yl-pentanoate (19) and 17a-oxa-d-homoandrost-5-en-17-one-3β-yl-hexanoate (20) with a therapeutic potential as antiandrogens.The biological effect of these steroids was demonstrated in in vivo as well as in vitro experiments. In the in vivo experiments, we measured the activity of ten new steroidal derivatives on the weight of the prostate and seminal vesicle glands of gonadectomized hamsters treated with testosterone. For the in vitro studies, we determined the IC50 values by measuring the concentration of the steroidal derivatives that inhibits 50% of the activity of the 5α-reductase enzyme present in human prostate and also its binding capacity to the androgen receptors (AR) obtained from rat's prostate cytosol. The results from these experiments indicated that compounds 11–20, significantly decreased the weight of the prostate and seminal vesicles as compared to testosterone treated animals; this reduction of the weight of these glands was comparable to that produced by Finasteride. On the other hand, compounds 11–20 inhibited the enzyme 5α-reductase, with compounds 14–19 (IC50 values of 4.2 ± 0.95, 0.025 ± 0.003, 1.2 ± 0.45, 1.2 ± 0.1, 0.028 ± 0.003, and 0.069 ± 0.005 nM, respectively) showing the highest inhibitory activity. The results from the in vitro experiments indicated that only 15–17 bind to the AR.

Graphical abstractNew steroidal lactones as inhibitors of human prostatic's 5α-reductase enzyme and for binding to the androgen receptors. In vivo activity.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The steroidal lactones produced pharmacological effect as antiandrogens. ► The lactones 15, 18 and 19 inhibited with high potency the 5α-reductase activity. ► The steroidal lactones 15–17 showed a low affinity for the androgen receptor. ► Novel steroidal lactones have a therapeutic potential as antiandrogens.