title: A new avenue toward androgen receptor pan-antagonists: C2 sterically hindered substitution of hydroxy-propanamides.
abstract: 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.
authors.affiliation: Institute for the Organic Synthesis and Photoreactivity, Italian National Research Council , Via Gobetti 101, 40129 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Guerrini
authors.forename: Anna
authors.initials: A
authors.lastname: Tesei
authors.forename: Claudia
authors.initials: C
authors.lastname: Ferroni
authors.forename: Giulia
authors.initials: G
authors.lastname: Paganelli
authors.forename: Alice
authors.initials: A
authors.lastname: Zamagni
authors.forename: Silvia
authors.initials: S
authors.lastname: Carloni
authors.forename: Marzia
authors.initials: M
authors.lastname: Di Donato
authors.forename: Gabriella
authors.initials: G
authors.lastname: Castoria
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Beretta
authors.forename: Alberto
authors.initials: A
authors.lastname: Del Rio
authors.forename: Greta
authors.initials: G
authors.lastname: Varchi
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011487:Protein Conformation / Q000187:drug effects; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen