Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1 |
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| Authors: | Jing Zhang Qiu-Sha Pan Xing-Kai Qian Xiang-Lu Zhou Ya-Jie Wang Rong-Jing He Le-Tian Wang Yan-Ran Li Hong Huo Cheng-Gong Sun Lei Sun Li-Wei Zou Ling Yang |
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| Institution: | aInstitute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China;bTranslational Medicine Research Center, Guizhou Medical University, Guizhou, China;cDalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China;dThe Second Hospital of Dalian Medical University, Dalian, China |
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| Abstract: | Pancreatic lipase (PL) is a well-known key target for the prevention and treatment of obesity. Human carboxylesterase 1A (hCES1A) has become an important target for the treatment of hyperlipidaemia. Thus, the discovery of potent dual-target inhibitors based on PL and hCES1A hold great potential for the development of remedies for treating related metabolic diseases. In this study, a series of natural triterpenoids were collected and the inhibitory effects of these triterpenoids on PL and hCES1A were determined using fluorescence-based biochemical assays. It was found that oleanolic acid (OA) and ursolic acid (UA) have the excellent inhibitory effects against PL and hCES1A, and highly selectivity over hCES2A. Subsequently, a number of compounds based on the OA and UA skeletons were synthesised and evaluated. Structure–activity relationship (SAR) analysis of these compounds revealed that the acetyl group at the C-3 site of UA (compound 41) was very essential for both PL and hCES1A inhibition, with IC50 of 0.75 µM and 0.014 µM, respectively. In addition, compound 39 with 2-enol and 3-ketal moiety of OA also has strong inhibitory effects against both PL and hCES1A, with IC50 of 2.13 µM and 0.055 µM, respectively. Furthermore, compound 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, butyrylcholinesterase (BChE) and dipeptidyl peptidase IV (DPP-IV). Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, we found two triterpenoid derivatives with strong inhibitory ability on both PL and hCES1A, which can be served as promising lead compounds for the development of more potent dual-target inhibitors targeting on PL and hCES1A. |
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| Keywords: | Triterpenoids pancreatic lipase human carboxylesterase 1 dual inhibitors adipocyte adipogenesis |
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