1250441-07-6Relevant articles and documents
A new avenue toward androgen receptor pan-antagonists: C2 sterically hindered substitution of hydroxy-propanamides
Guerrini, Andrea,Tesei, Anna,Ferroni, Claudia,Paganelli, Giulia,Zamagni, Alice,Carloni, Silvia,Di Donato, Marzia,Castoria, Gabriella,Leonetti, Carlo,Porru, Manuela,De Cesare, Michelandrea,Zaffaroni, Nadia,Beretta, Giovanni Luca,Del Rio, Alberto,Varchi, Greta
, p. 7263 - 7279 (2015/01/30)
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.
