title: Discovery, synthesis, and structure-activity relationships of 20S-dammar-24-en-2α,3β,12β,20-tetrol (GP) derivatives as a new class of AMPKα2β1γ1 activators.
abstract: As a follow-up discovery of AMPK activators from natural products, 20S-dammar-24-en-2α,3β,12β,20-tetrol (GP, 1), a dammarane-type triterpenoid, was found to have some favorable metabolic effects on dyslipidemia in Golden Syrian hamsters, and activate AMPKα2β1γ1 by around 2.4 fold with an EC50 of 5.1μM on molecular level. In order to enhance its potency at AMPK and structure-activity relationship study, GP derivatives were designed, synthesized, and evaluated in pharmacological AMPK activation assays. Structure-activity relationship analysis showed that amine at the 24-position (groups I-IV) effectively and significantly increased the potency and efficacy. GP derivatives 12 and 17-19 exhibited better potency (EC50: 0.3, 0.8, 0.8, and 1.0μM) and efficacy (fold: 3.2, 2.7, 3.0, and 2.8) in the activation of AMPK heterotrimer α2β1γ1 than positive control (AMP, EC50: 1.6μM, fold: 3.2). Furthermore, the most potent compounds 12 and 17 obviously inhibited glucose output through increasing the phosphorylation of AMPK, without affecting mitochondrial membrane potential or producing cytotoxicity.
authors.affiliation: State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Chenhuan
authors.initials: C
authors.lastname: Dong
authors.affiliation: State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Xie
authors.affiliation: State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: liujunhua1985@126.com.
authors.forename: Junhua
authors.initials: J
authors.lastname: Liu
authors.affiliation: State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jyli@mail.shcnc.ac.cn.
authors.forename: Jingya
authors.initials: J
authors.lastname: Li
authors.affiliation: State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: lhhu@simm.ac.cn.
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D000097669:Dammaranes
chemical_list: D055372:AMP-Activated Protein Kinases; D005947:Glucose; D011994:Recombinant Proteins; D014315:Triterpenes; D000097669:Dammaranes; C526181:PRKAA2 protein, human; C526182:PRKAB1 protein, human; C526222:PRKAG1 protein, human
keywords: AMPK; AMPK heterotrimer α2β1γ1; Activators; Dammarane-type; Gynostemma yixingense; Structure–activity relationships