Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, Japan.
Bioorg Med Chem. 2011 Jun 1;19(11):3540-8. doi: 10.1016/j.bmc.2011.04.017. Epub 2011 Apr 20.
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.
一种有效的雄激素受体（AR）拮抗剂，3-（12-羟甲基-1,12-二碳硼烷-1-基）苯甲腈（3a，BA341），含有一个 p-碳硼烷笼作为疏水性药效团。我们通过单晶 X 射线衍射分析阐明了 3a 的结构性质，并对 3a 与 hAR LBD 进行了对接研究。3a 的氰基与 Gln711 和 Arg752 形成氢键，而羟甲基与 hAR LBD 中的 Asn705 和 Thr877 形成氢键。庞大的 p-碳硼烷笼被容纳在 hAR LBD 的疏水性口袋中。为了了解 3a 羟甲基周围的结构-活性关系，我们设计、合成并评估了各种新型 AR 配体的生物学活性。由于羰基化合物 8a、8b 和 8c 的生物学活性与母体羟基化合物 3a、7a 和 7b 的相似或较弱，因此似乎不仅需要与 hAR LBD 有效相互作用的羟甲基的相邻的氢键受体，而且还需要氢键供体。
