Replacement of nitro function by free boronic acid in non-steroidal anti-androgens†

Abstract

A new series of potential flutamide-like antiandrogens has been designed and synthesized to treat prostate cancer. This new series results from our research, which has been aimed at discovering new compounds that can be used for androgen deprivation treatment. The antiandrogens were designed and synthesized by varying the acyl part, linker, and substitution of the benzene ring in the 4-nitro-3-trifluoromethylanilide scaffold of non-steroidal androgens. In addition, the characteristic feature of the nitro group was replaced by a boronic acid functionality. Compound 9a was found to be more effective against LAPC-4 than the standard antiandrogens flutamide, hydroxyflutamide, and bicalutamide. Moreover, it exhibited lower toxicity against the non-cancerous cell line HK-2. The initial in silico study did not show evidence of covalent bonding to the androgen receptor, which was confirmed by an NMR binding experiment with arginine methyl ester. The structure–activity relationships discovered in this study could provide directions for further research on non-steroidal antiandrogens.