4.7 Article

Crystal structure, docking study and structure-activity relationship of carborane-containing androgen receptor antagonist 3-(12-hydroxymethyl-1,12-dicarba-closo-dodecaboran-1-yl)benzonitrile

Journal

BIOORGANIC & MEDICINAL CHEMISTRY
Volume 19, Issue 11, Pages 3540-3548

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.04.017

Keywords

Androgen receptor; Antagonist; Carborane; X-ray crystallography; Docking study; Structure-activity study

Funding

  1. Ministry of Education, Culture, Sports, Science and Technology, Japan [20390035]
  2. Grants-in-Aid for Scientific Research [20390035, 23790128, 21790116] Funding Source: KAKEN

Ask authors/readers for more resources

A potent androgen receptor (AR) antagonist, 3-(12-hydroxymethyl-1,12 dicarba-closo-dodecaboran-1-yl) benzonitrile (3a, BA341), contains a p-carborane cage as a hydrophobic pharmacophore. We elucidated the structural properties of 3a by means of single-crystal X-ray diffraction analysis and conducted a docking study of 3a with hAR LBD. The cyano group of 3a formed hydrogen bonds with Gln711 and Arg752 and the hydroxymethyl group did so with Asn705 and Thr877 in hAR LBD. The bulky p-carborane cage was accommodated in the hydrophobic pocket of hAR LBD. To understand the structure-activity relationship around the hydroxymethyl group of 3a, we designed, synthesized, and evaluated the biological activities of various novel AR ligands. Since the biological activities of carbonyl compounds 8a, 8b, and 8c were similar to or weaker than those of the parent hydroxyl compounds 3a, 7a, and 7b, it seems to be necessary to have not only a hydrogen bonding acceptor, but also a hydrogen bonding donor adjacent to the hydroxymethyl group of 3a for efficient interaction with hAR LBD. (C) 2011 Elsevier Ltd. All rights reserved.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available