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

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posted on 08.03.2017, 00:00 by Claudia Ferroni, Antonella Pepe, Yeong Sang Kim, Sunmin Lee, Andrea Guerrini, Marco Daniele Parenti, Anna Tesei, Alice Zamagni, Michela Cortesi, Nadia Zaffaroni, Michelandrea De Cesare, Giovanni Luca Beretta, Jane B. Trepel, Sanjay V. Malhotra, Greta Varchi
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.