Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents

doi:10.1007/s13659-015-0062-6

Natural Products and Bioprospecting ›› 2015, Vol. 5 ›› Issue (3): 129-157.DOI: 10.1007/s13659-015-0062-6

• Original article • Previous Articles Next Articles

Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents

Kun Wei¹, Gang-Qiang Wang^1,2, 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

Received:2015-04-21 Revised:2015-05-20 Online:2018-02-11 Published:2015-06-24
Supported by:
The authors are grateful to the National Natural Science Foundation of China(81102348, U1132607, 81373289).

Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents

Kun Wei¹, Gang-Qiang Wang^1,2, 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

基金资助:
The authors are grateful to the National Natural Science Foundation of China(81102348, U1132607, 81373289).

Abstract

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.

Key words: Natural products, Structure optimization, Antiobesity agents, Pancreatic lipase inhibitors, Vibralactone derivatives

摘要： 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.

关键词: Natural products, Structure optimization, Antiobesity agents, Pancreatic lipase inhibitors, Vibralactone derivatives

Kun Wei, Gang-Qiang Wang, Xue Bai, Yan-Fen Niu, He-Ping Chen, Chun-Nan Wen, Zheng-Hui Li, Ze-Jun Dong, Zhi-Li Zuo, Wen-Yong Xiong, Ji-Kai Liu. Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents[J]. Natural Products and Bioprospecting, 2015, 5(3): 129-157.

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Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents

Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents

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