Design and synthesis of androgen receptor full antagonists bearing a p-carborane cage: promising ligands for anti-androgen withdrawal syndrome.

Pure androgen receptor (AR) full antagonists are candidates to treat anti-androgen refractory prostate cancers. We previously developed a carborane-containing AR antagonist, 3-(12-hydroxymethyl-1,12-dicarba-closo-dodecaborane-1-yl)benzonitrile (BA341), which was more potent than hydroxyflutamide (4) but acted as an agonist toward LNCaP prostate cancer cells expressing T877A AR mutant. Here, we designed and synthesized novel AR full antagonists structurally based upon the clinically used AR full antagonist (R)-bicalutamide (5) to test our hypothesis that the carborane cage is suitable as a hydrophobic pharmacophore for AR ligands. Compounds 7b and 8b showed good biological profiles in AR binding and transactivation assays and dose-dependently inhibited the testosterone-induced proliferation of LNCaP cells, as well as SC-3 cells. The IC(50) values of compounds 7b and 8b were 3.8 x 10(-7) and 4.2 x 10(-7) M, respectively [5, 8.7 x 10(-7) M]. Since compounds 7b and 8b did not show any agonistic activity in functional assays, they seem to be pure AR full antagonists and are therefore candidates for treatment of anti-androgen withdrawal syndrome.