1,4-Substituted Triazoles as Nonsteroidal Anti-Androgens for Prostate Cancer Treatment

Prostate cancer (PC) is the fifth
leading cause of cancer death in men, and the androgen receptor (AR)
represents the primary target for PC treatment, even though the disease
frequently progresses toward androgen-independent forms. Most of the
commercially available nonsteroidal antiandrogens show a common scaffold
consisting of two aromatic rings connected by a linear or a cyclic
spacer. By taking advantage of a facile, one-pot click chemistry reaction,
we report herein the preparation of a small library of novel 1,4-substituted
triazoles with AR antagonistic activity. Biological and theoretical
evaluation demonstrated that the introduction of the triazole core
in the scaffold of nonsteroidal antiandrogens allowed the development
of small molecules with improved overall AR-antagonist activity. In
fact, compound 14d displayed promising in vitro antitumor activity toward three
different prostate cancer cell lines and was able to induce 60% tumor
growth inhibition of the CW22Rv1 in vivo xenograft model. These results
represent a step toward the development of novel and improved AR antagonists.