Chemical synthesis and biological activities of 16α-derivatives of 5α-androstane-3α,17β-diol as antiandrogens

In our efforts to develop compounds with therapeutic potential as antiandrogens, we synthesized a series of 5α-androstane-3α,17β-diol derivatives with a fixed side-chain length of 3-methylenes at C-16α, but bearing a diversity of functional groups at the end. Among these, the chloride induced the best antiproliferative activity on androgen-sensitive Shionogi cells. Substituting the OH at C-3 by a methoxy group showed the importance of the OH. Moreover, its transformation into a ketone increased the androgen receptor (AR) binding but decreased the antiproliferative activity and induced a proliferative effect on Shionogi cells. These results confirm the importance of keeping a 5α-androstane-3α,17β-diol nucleus instead of a dihydrotestosterone nucleus. Variable side-chain lengths of 2-, 3-, 4-, and 6-methylenes at C-16α were investigated and the optimal length was found to be 3-methylenes. Although exhibiting a weak AR binding affinity, 16α-(3′-chloropropyl)-5α-androstane-3α,17β-diol (15) provided an antiproliferative activity on Shionogi cells similar to that of pure non-steroidal antiandrogen hydroxy-flutamide (77% and 67%, respectively, at 0.1 μM). The new steroidal compound, 15, thus constitutes a good starting point for development of future antiandrogens with a therapeutic potential against prostate cancer.

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