Novel androgen receptor full antagonists: Design, synthesis, and a docking study of glycerol and aminoglycerol derivatives that contain p -carborane cages
Novel androgen receptor full antagonists: Design, synthesis, and a docking study of glycerol and aminoglycerol derivatives that contain p -carborane cages
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新型雄激素受体完全拮抗剂：含有对碳硼烷笼的甘油和氨基甘油衍生物的设计、合成和对接研究
DOI：
10.1016/j.bmc.2018.06.007
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发表时间：
2018
影响因子：
3.5
通讯作者：
Endo Yasuyuki
中科院分区：
文献类型：
--
作者：
Kaise Asako;Ohta Kiminori;Fujii Shinya;Oda Akifumi;Goto Tokuhito;Endo Yasuyuki
基于比卡鲁胺与T877 A突变的雄激素受体（AR）的共晶结构，设计并合成了甘油和氨基甘油衍生物作为新型含碳硼烷的AR调节剂。6c的（R）-异构体（其手性来源于甘油基团）对表达T877 A突变的AR的LNCaP细胞系显示出比相应的（S）-异构体高20倍的有效细胞抑制活性。两种异构体与AR的对接研究表明，（R）-6顺式比（S）-6 c更接近AR的螺旋-12，这是AR二级结构中表达拮抗活性的最重要的共同基序。
Based on the co-crystal structure of bicalutamide with a T877A-mutated androgen receptor (AR), glycerol and aminoglycerol derivatives were designed and synthesized as a novel type of carborane-containing AR modulators. The (R)-isomer of6c, whose chirality is derived from the glycerol group, showed 20 times more potent cell inhibitory activity against LNCaP cell lines expressing T877A-mutated AR than the corresponding (S)-isomer. Docking studies of both isomers with AR suggested that (R)-6cis in closer spatial proximity to helix-12 of the AR than (S)-6c, which is the most important common motif in the secondary structure of AR for the expression of antagonistic activity.