Structural Modification of Natural Product Ganomycin I Leading to Discovery of a α-Glucosidase and HMG-CoA Reductase Dual Inhibitor Improving Obesity and Metabolic Dysfunction in Vivo

  • J Med Chem. 2018 Apr 26;61(8):3609-3625. doi: 10.1021/acs.jmedchem.8b00107.
Kai Wang  1 ,  Li Bao  1 ,  Nan Zhou ,  Jinjin Zhang  1 ,  Mingfang Liao  1 ,  Zhongyong Zheng  1 ,  Yujing Wang  1 ,  Chang Liu ,  Jun Wang ,  Lifeng Wang  2 ,  Wenzhao Wang ,  ShuangJiang Liu  1 ,  Hongwei Liu  1
Affiliations
  • 1. University of Chinese Academy of Sciences , Beijing 100049 , P. R. China.
  • 2. Beijing Kangyuan Pharmaceutical Co., Ltd ., No. 3 Changliu Road , Changping District, Beijing 102200 , P. R. China.
PMID: 29634260 DOI: 10.1021/acs.jmedchem.8b00107
Abstract

It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving Insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene Sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.

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