title: Synthesis and evaluation of novel oleanolic acid derivatives as potential antidiabetic agents.
abstract: Antidiabetic agents simultaneously inhibiting hepatic glucose production and stimulating hepatic glucose consumption could apply a better control over hyperglycemia. A series of oleanolic acid derivatives with bulky substituents at C-3 position were designed and synthesized in order to search for this kind of agents. All of the compounds were evaluated biologically in vitro using glycogen phosphorylase and HepG2 cells. The results indicated that several derivatives exhibited moderate-to-good inhibitory activities against glycogen phosphorylase. Compound 8g showed the best inhibition with an IC50 value of 5.4 μm. Moreover, most of the derivatives were found to increase the glucose consumption in HepG2 cells in a dose-dependent manner. The possible binding mode of compound 8g with glycogen phosphorylase was also explored by docking study. 8g was found to have hydrogen bonding interactions with Arg193, Arg310, and Arg60 of the allosteric site.
authors.affiliation: Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde, 067000, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Jia
authors.forename: Jizhe
authors.initials: J
authors.lastname: Dong
authors.forename: Dongyin
authors.initials: D
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Wen
mesh_terms: D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C000592737:3-(2-(4-(2-naphthalen-1-yl)acetoxymethyl-1H-1,2,3-triazol-1-yl)acetoxy)olean-12-en-28-oic acid; D007004:Hypoglycemic Agents; D014230:Triazoles; D009828:Oleanolic Acid; D024981:Glycogen Phosphorylase; D005947:Glucose
keywords: binding mode; glycogen phosphorylase inhibitors; hepatic glucose consumption; hepatic glucose production; oleanolic acid