A new avenue toward androgen receptor pan-antagonists: C2 sterically hindered substitution of hydroxy-propanamides

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

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)7263-7279
Number of pages17
JournalJournal of Medicinal Chemistry
Issue number17
StatePublished - Sep 11 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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