Design, synthesis and biological evaluation of peptidyl-prolyl cis-trans isomerase Pin1 inhibitors
10.16438/j.0513-4870.2020-1333
- VernacularTitle:肽脯氨酰顺反异构酶Pin1抑制剂的设计、合成及活性研究
- Author:
Kun LI
1
;
Qun NIU
2
;
Qi-hao XU
2
;
Yu HAN
2
;
Dan LIU
2
;
Lin-xiang ZHAO
2
Author Information
1. Department of Pharmacy, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou 450003, China
2. Key Laboratory of Structure-Based Drugs Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, China
- Publication Type:Research Article
- Keywords:
Pin1 inhibitor;
benzimidazole;
prostate cancer;
molecular docking
- From:
Acta Pharmaceutica Sinica
2020;55(11):2679-2687
- CountryChina
- Language:Chinese
-
Abstract:
Peptidyl-prolyl cis-trans isomerase Pin1 is over-expressed in prostate cancer cells and the level of expression correlates with the malignancy grade and prognosis in patients. In this work, twenty-one 2-(1H-benzimidazol-2-ylthio) acetic acid derivatives were designed and prepared with the aid of the crystal structure of Pin1 and our previous work. The chemical structures of the target compounds were confirmed by 1H NMR, 13C NMR, ESI-MS and IR. The inhibitory activity of compounds 6a-6i and 13a-13i against Pin1 were determined using a protease-coupled assay. The results indicated that twenty compounds were significantly superior to the positive control drug Juglone, and 6g, 6h and 13i exhibited the most potent Pin1 inhibitory activity, with IC50 values at the sub-micromolar level. The in vitro anti-proliferative activities of these analogs were evaluated by the MTT assay and several showed a moderate effect in human prostate cancer PC-3 cells. Molecular docking studies demonstrated that both the benzimidazole skeleton and the thioacetic acid fragment were indispensable for the compounds to interact with key residues in the catalytic domain of Pin1.
