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Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents |
| Kun Wei1, Gang-Qiang Wang1,2, Xue Bai1, Yan-Fen Niu1, He-Ping Chen1, Chun-Nan Wen1, Zheng-Hui Li1, Ze-Jun Dong1, Zhi-Li Zuo1, Wen-Yong Xiong1, Ji-Kai Liu1 |
1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China;
2. School of Nuclear Technology and Chemistry & Biology, Hubei University of Science and Technology, Xianning 437100, China |
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Abstract The unusual fused β-lactone vibralactone was isolated from cultures of the basidiomycete Boreostereum vibrans and has been shown to significantly inhibit pancreatic lipase. In this study, a structure-based lead optimization of vibralactone resulted in three series of 104 analogs, among which compound C1 exhibited the most potent inhibition of pancreatic lipase, with an IC50 value of 14 nM. This activity is more than 3000-fold higher than that of vibralactone. The effect of compound C1 on obesity was investigated using high-fat diet(HFD)-induced C57BL/6 J obese mice. Treatment with compound C1 at a dose of 100 mg/kg significantly decreased HFD-induced obesity, primarily through the improvement of metabolic parameters, such as triglyceride levels.
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| Keywords
Natural products
Structure optimization
Antiobesity agents
Pancreatic lipase inhibitors
Vibralactone derivatives
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| Fund:The authors are grateful to the National Natural Science Foundation of China(81102348, U1132607, 81373289). |
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Issue Date: 11 February 2018
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