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

• Published in: European journal of medicinal chemistry Vol. 127; pp. 1035 - 1046
• Main Authors: Wang, Kai, Bao, Li, Ma, Ke, Zhang, Jinjin, Chen, Baosong, Han, Junjie, Ren, Jinwei, Luo, Huajun, Liu, Hongwei
• Format: Journal Article
• Language: English
• Published: France 15.02.2017
• Subjects: Adipose Tissue - drug effects; Adipose Tissue - metabolism; Alanine Transaminase - metabolism; alpha-Glucosidases - chemistry; alpha-Glucosidases - 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; Ganoderma leucocontextum; α-Glucosidase inhibition; Meroterpenes; Anti-diabetic activities; HMG-CoA reductase inhibition
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.11.015

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 mice.