Novel androgen receptor full antagonists: Design, synthesis, and a docking study of glycerol and aminoglycerol derivatives that contain p-carborane cages

作者：Kaise Asako; Ohta Kiminori^*; Fujii Shinya; Oda Akifumi; Goto Tokuhito; Endo Yasuyuki

来源：Bioorganic & Medicinal Chemistry, 2018, 26(13): 3805-3811.

DOI：10.1016/j.bmc.2018.06.007

• Androgen receptor
• Hydrophobic pharmacophore
• Carborane
• Anti-androgen withdrawal syndrome

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 of 6c, 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)-6c is 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.

• 出版日期2018-7-30