Chiral nonsteroidal affinity ligands for the androgen receptor. 1. Bicalutamide analogues bearing electrophilic groups in the B aromatic ring

A series of chiral analogues of bicalutamide bearing electrophilic groups ( isothiocyanate, N-chloroacetyl, and N-bromoacetyl) on aromatic ring B of th e parent molecule were synthesized. These compounds were designed as affini ty ligands for the androgen receptor (AR). We prepared the (R)- and (S)-opt ical isomers of these compounds as pure enantiomers. The AR binding affinit ies of these compounds were measured in a competitive binding assay with th e radiolabeled high-affinity AR ligand, [H-3]mibolerone. In accordance with our previous results for the enantiomers of bicalutamide, we found that al l (R)-isomers demonstrated much higher binding affinity to the AR as compar ed to their corresponding (S)-isomers. The para-substituted affinity ligand s in ring B bound the AR with higher affinities than the corresponding meta -substituted analogues. Oxidation of thioester affinity ligands to their su lfonyl analogues for the para-substituted compounds decreased AR binding af finities and similar modification increased binding affinities for correspo nding meta-analogues. The least potent para-substituted sulfonyl compounds had higher AR binding affinities than the most potent meta-substituted sulf onyl compounds. Overall, the para-substituted unoxidized molecules demonstr ated the highest AR binding affinity. Subsequent research using AR exchange assays and Scatchard analyses showed that the isothiocyanate affinity liga nds (R)-7, (R)-9, and (R)-10 reported herein are the first specific chemoaf finity ligands for the AR.