A New Avenue toward Androgen Receptor Pan-antagonists: C2 Sterically Hindered Substitution of Hydroxy-propanamides
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- 作者：Andrea Guerrini ; Anna Tesei ; Claudia Ferroni ; Giulia Paganelli ; Alice Zamagni ; Silvia Carloni ; Marzia Di Donato ; Gabriella Castoria ; Carlo Leonetti ; Manuela Porru ; Michelandrea De Cesare ; Nadia Zaffaroni ; Giovanni Luca Beretta ; Alberto Del Rio ; Greta Varchi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：September 11, 2014
- 年：2014
- 卷：57
- 期：17
- 页码：7263-7279
- 全文大小：990K
- ISSN：1520-4804
文摘
The androgen receptor (AR) represents the primary target for prostate cancer (PC) treatment even when the disease progresses toward androgen-independent (AIPC) or castration-resistant (CRPC) forms. Because small chemical changes in the structure of nonsteroidal AR ligands determine the pharmacological responses of AR, we developed a novel stereoselective synthetic strategy that allows sterically hindered C2-substituted bicalutamide analogues to be obtained. Biological and theoretical evaluations demonstrate that C2-substitution with benzyl and phenyl moieties is a new, valuable option toward improving pan-antagonist behavior. Among the synthesized compounds, (R)-16m, when compared to casodex, (R)-bicalutamide, and enzalutamide, displayed very promising in vitro activity toward five different prostate cancer cell lines, all representative of CPRC and AIPC typical mutations. Despite being less active than (R)-bicalutamide, (R)-16m also displayed marked in vivo antitumor activity on VCaP xenografts and thus it may serve as starting point for developing novel AR pan-antagonists.