Design, synthesis and biological evaluation of ring A modified 11-keto-boswellic acid derivatives as Pin1 inhibitors with remarkable anti-prostate cancer activity

作者：Huang, Min; Li, Aihua; Zhao, Feng; Xie, Xiaorui; Li, Kun; Jing, Yongkui; Liu, Dan^*; Zhao, Linxiang^*

来源：Bioorganic & Medicinal Chemistry Letters, 2018, 28(19): 3187-3193.

DOI：10.1016/j.bmcl.2018.08.021

• Pin1 inhibitors
• 11-Keto-boswellic acid
• Anticancer
• Cell cycle arrest

Pin1 (Protein interaction with never in mitosis A1) is a validated molecular target for anticancer drug discovery. Herein, we reported the design, synthesis, and structure-activity relationship study of novel ring A modified AKBA (3-acetyl-11-keto-boswellic acid) derivatives as Pin1 inhibitors. Most compounds showed superior Pin1 inhibitory activities to AKBA. One of the most promising compounds, 10a, potently inhibited Pin1 with IC50 value of 0.46 mu M, while it displayed excellent anti-proliferative effect against prostate cancer cells PC-3 with GI(50) value of 1.82 mu M. Structure-activity relationship indicated that reasonable structural modifications in ring A had significant impact on improving activity. Further mechanism research revealed that 10a decreased the level of Cyclin D1 and caused cell cycle arrest at G0/G1 phase in PC-3 cancer cells. Thus, compound 10a may serve as potential anti-prostate cancer agent for further investigation through Pin1 inhibition.

• 出版日期2018-10-15
• 单位沈阳药科大学