Portal de Periódicos da CAPES

Acidic heterocycles as novel hydrophilic pharmacophore of androgen receptor ligands with a carborane core structure

2008; Elsevier BV; Volume: 17; Issue: 1 Linguagem: Inglês

10.1016/j.bmc.2008.10.060

1464-3391

Shinya Fujii, Kiminori Ohta, Tokuhito Goto, Hiroyuki Kagechika, Yasuyuki Endo,

Prostate Cancer Treatment and Research

A novel series of androgen receptor (AR) ligands bearing an acidic heterocycle with hydrogen-bonding ability as the terminal polar group was developed. Since most non-steroidal AR ligands so far known are structurally limited to nitro- or cyanobenzanilide as the polar pharmacophore, development of alternative hydrogen-bonding components is required to obtain novel AR ligands. Various acidic heterocycles were introduced into a hydrophobic phenylcarborane (1-phenyl-1,12-dicarba-closo-dodecaborane) core structure to provide a moiety that could interact effectively with the critical basic arginine residue of the AR ligand binding domain. The most potent compounds, 1,2,4-oxadiazole-5-thione derivatives 21a and 21b, exhibited higher affinity for hAR than did the well-known anti-androgen hydroxyflutamide. The results suggest that this heterocyclic functionality is potential bioisoster of the nitro and cyano groups forming the polar pharmacophores of known non-steroidal AR ligands.