Design, synthesis and biological evaluation of ring A modified 11-keto-boswellic acid derivatives as Pin1 inhibitors with remarkable anti-prostate cancer activity. Issue 19 (15th October 2018)

• Record Type: Journal Article
• Authors: Huang, Min; Li, Aihua; Zhao, Feng; Xie, Xiaorui; Li, Kun; Jing, Yongkui; Liu, Dan; Zhao, Linxiang
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 19(2018)
• Page Start: 3187
• Page End: 3193
• Publication Date: 2018-10-15
• Subjects: Pin1 inhibitors -- 11-Keto-boswellic acid -- Anticancer -- Cell cycle arrest; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.08.021
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A novel series of 11-keto-boswellic acid derivatives were designed and synthesized as Pin1 inhibitors. 10a showed excellent Pin1 inhibitory activity. 10a displayed most potent anti-proliferative effect against PC-3 cancer cells. 10a downregulated the level of Cyclin D1 and caused cell cycle arrest. Docking studies revealed strong interaction between10a and Pin1 in the PPIase domain. 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 IC50 value of 0.46 μM, while it displayed excellent anti-proliferative effect against prostate cancer cells PC-3 with GI50 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 that10a decreased the level of Cyclin D1 and caused cell cycle arrest at G0/G1 phase in PC-3 cancer cells. Thus, compound10a may serve as potential anti-prostate cancer agent for further investigation through Pin1 inhibition.