Open Access1,4-Substituted Triazoles as Nonsteroidal Anti-Androgens for Prostate Cancer Treatment
Author(s) -
Claudia Ferroni,
Antonella Pepe,
Yeong Sang Kim,
Sunmin Lee,
Andrea Guerrini,
Marco Parenti,
Anna Tesei,
Alice Zamagni,
Michela Cortesi,
Nadia Zaffaroni,
Michelandrea De Cesare,
Giovanni Luca Beretta,
Jane B. Trepel,
Sanjay V. Malhotra,
Greta Varchi
Publication year - 2017
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.7b00105
Subject(s) - antiandrogens , chemistry , nonsteroidal , androgen receptor , prostate cancer , in vivo , prostate , scaffold , in vitro , antiandrogen , antagonist , triazole , cancer research , biological activity , pharmacology , small molecule , androgen , cancer , receptor , medicine , hormone , biochemistry , biology , microbiology and biotechnology , organic chemistry , biomedical engineering
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.