A novel class of α-glucosidase and HMG-CoA reductase inhibitors from Ganoderma leucocontextum and the anti-diabetic properties of ganomycin I in KK-Ay mice

Kai Wang; Li Bao; Ke Ma; Jinjin Zhang; Baosong Chen; Junjie Han; Jinwei Ren; Huajun Luo; Hongwei Liu

doi:10.1016/j.ejmech.2016.11.015

A novel class of α-glucosidase and HMG-CoA reductase inhibitors from Ganoderma leucocontextum and the anti-diabetic properties of ganomycin I in KK-A^y mice

Eur J Med Chem. 2017 Feb 15:127:1035-1046. doi: 10.1016/j.ejmech.2016.11.015. Epub 2016 Nov 9.

Authors

Kai Wang¹, Li Bao², Ke Ma¹, Jinjin Zhang¹, Baosong Chen¹, Junjie Han², Jinwei Ren², Huajun Luo³, Hongwei Liu⁴

Affiliations

¹ State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, No.1 Beichenxi Road, Chaoyang District, Beijing 100101, PR China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, PR China.
² State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, No.1 Beichenxi Road, Chaoyang District, Beijing 100101, PR China.
³ Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Science, China Three Gorges University, Yichang, 443002, PR China.
⁴ State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, No.1 Beichenxi Road, Chaoyang District, Beijing 100101, PR China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: liuhw@im.ac.cn.

PMID: 27839787
DOI: 10.1016/j.ejmech.2016.11.015

Abstract

Three new meroterpenoids, ganoleucin A-C (1-3), together with five known meroterpenoids (4-8), were isolated from the fruiting bodies of Ganoderma leucocontextum. The structures of the new compounds were elucidated by extensive spectroscopic analysis, circular dichroism (CD) spectroscopy, and chemical transformation. The inhibitory effects of 1-8 on HMG-CoA reductase and α-glucosidase were tested in vitro. Ganomycin I (4), 5, and 8 showed stronger inhibitory activity against HMG-CoA reductase than the positive control atorvastatin. Compounds 1, and 3-8 presented potent noncompetitive inhibitory activity against α-glucosidase from both yeast and rat small intestinal mucosa. Ganomycin I (4), the most potent inhibitor against both α-glucosidase and HMG-CoA reductase, was synthesized and evaluated for its in vivo bioactivity. Pharmacological results showed that ganomycin I (4) exerted potent and efficacious hypoglycemic, hypolipidemic, and insulin-sensitizing effects in KK-A^y mice.

Keywords: Anti-diabetic activities; Ganoderma leucocontextum; HMG-CoA reductase inhibition; Meroterpenes; α-Glucosidase inhibition.

MeSH terms

Adipose Tissue / drug effects
Adipose Tissue / metabolism
Alanine Transaminase / metabolism
Animals
Aspartate Aminotransferases / metabolism
Blood Glucose / metabolism
Body Weight / drug effects
Female
Ganoderma / chemistry*
Glycogen / metabolism
Glycoside Hydrolase Inhibitors / chemistry
Glycoside Hydrolase Inhibitors / isolation & purification
Glycoside Hydrolase Inhibitors / metabolism
Glycoside Hydrolase Inhibitors / pharmacology*
Hydroquinones / chemistry
Hydroquinones / isolation & purification
Hydroquinones / metabolism
Hydroquinones / pharmacology*
Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemistry
Hydroxymethylglutaryl-CoA Reductase Inhibitors / isolation & purification
Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / isolation & purification
Hypoglycemic Agents / metabolism
Hypoglycemic Agents / pharmacology*
Insulin Resistance
Kinetics
Liver / drug effects
Liver / metabolism
Male
Mice
Molecular Docking Simulation
Protein Conformation
alpha-Glucosidases / chemistry
alpha-Glucosidases / metabolism*

Substances

Blood Glucose
Glycoside Hydrolase Inhibitors
Hydroquinones
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypoglycemic Agents
ganomycin I
Glycogen
Aspartate Aminotransferases
Alanine Transaminase
alpha-Glucosidases