1. 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
- Author
-
Hongwei Liu, Jinjin Zhang, Shuang-Jiang Liu, Nan Zhou, Zhongyong Zheng, Li Bao, Kai Wang, Chang Liu, Lifeng Wang, Mingfang Liao, Jun Wang, Yu-Jing Wang, and Wenzhao Wang
- Subjects
0301 basic medicine ,Male ,Swine ,Reductase ,Pharmacology ,Gut flora ,01 natural sciences ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Lactones ,Insulin resistance ,Drug Stability ,In vivo ,Drug Discovery ,medicine ,Animals ,Glycoside Hydrolase Inhibitors ,Obesity ,Meroterpene ,Metabolic Syndrome ,biology ,010405 organic chemistry ,Chemistry ,Terpenes ,alpha-Glucosidases ,medicine.disease ,biology.organism_classification ,0104 chemical sciences ,Gastrointestinal Microbiome ,Fatty Liver ,Mice, Inbred C57BL ,030104 developmental biology ,HMG-CoA reductase ,biology.protein ,Microsomes, Liver ,Molecular Medicine ,Female ,Hydroxymethylglutaryl CoA Reductases ,Anti-Obesity Agents ,Steatosis ,Metabolic syndrome ,Hydroxymethylglutaryl-CoA Reductase Inhibitors - 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.
- Published
- 2018