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

Abstract 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 IC 50 value of 0.46 μM, while it displayed excellent anti-proliferative effect against prostate cancer cells PC-3 with GI 50 value of 1.82 μM. 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.