Discovery, synthesis, and structure-activity relationships of 20S-dammar-24-en-2 alpha,3 beta,12 beta,20-tetrol (GP) derivatives as a new class of AMPK alpha 2 beta 1 gamma 1 activators
文献类型：期刊论文
| 作者 | Dong, Chenhuan; Xie, Zhifu; Yu, Yanyan; Li, Jia ; Liu, Junhua; Li, Jingya; Hu, Lihong
|
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2016-06-15 |
| 卷号 | 24期号:12页码:2688-2696 |
| 关键词 | Gynostemma yixingense Dammarane-type AMPK AMPK heterotrimer alpha 2 beta 1 gamma 1 Activators Structure-activity relationships |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2016.04.034 |
| 文献子类 | Article |
| 英文摘要 | As a follow-up discovery of AMPK activators from natural products, 20S-dammar-24-en-2 alpha,3 beta,12 beta,20-tetrol (GP, 1), a dammarane-type triterpenoid, was found to have some favorable metabolic effects on dyslipidemia in Golden Syrian hamsters, and activate AMPK alpha 2 beta 1 gamma 1 by around 2.4 fold with an EC50 of 5.1 mu M 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 1.0 mu M) and efficacy (fold: 3.2, 2.7, 3.0, and 2.8) in the activation of AMPK heterotrimer alpha 2 beta 1 gamma 1 than positive control (AMP, EC50: 1.6 mu M, 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. (C) 2016 Elsevier Ltd. All rights reserved. |
| WOS关键词 | PROTEIN-KINASE ; GYNOSTEMMA-PENTAPHYLLUM ; SKELETAL-MUSCLE ; ENERGY HOMEOSTASIS ; SIGNALING PATHWAYS ; DRUG TARGET ; AMPK ; RAT ; GLUCOSE ; CELLS |
| 资助项目 | National Natural Science Foundation of China[81402811] ; National Natural Science Foundation of China[81470166] ; National Natural Science Foundation of China[81561148011] ; Chinese National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program'[2013ZX09508104] ; Science Foundation of Shanghai[15431901100] ; Science Foundation of Shanghai[15DZ2291600] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000376727800010 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276000]  |
| 专题 | 国家新药筛选中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Liu, Junhua; Li, Jingya; Hu, Lihong |
| 作者单位 | Univ Chinese Acad Sci, Shanghai Inst Mat Med, State key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Dong, Chenhuan,Xie, Zhifu,Yu, Yanyan,et al. Discovery, synthesis, and structure-activity relationships of 20S-dammar-24-en-2 alpha,3 beta,12 beta,20-tetrol (GP) derivatives as a new class of AMPK alpha 2 beta 1 gamma 1 activators[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2016,24(12):2688-2696. |
| APA | Dong, Chenhuan.,Xie, Zhifu.,Yu, Yanyan.,Li, Jia.,Liu, Junhua.,...&Hu, Lihong.(2016).Discovery, synthesis, and structure-activity relationships of 20S-dammar-24-en-2 alpha,3 beta,12 beta,20-tetrol (GP) derivatives as a new class of AMPK alpha 2 beta 1 gamma 1 activators.BIOORGANIC & MEDICINAL CHEMISTRY,24(12),2688-2696. |
| MLA | Dong, Chenhuan,et al."Discovery, synthesis, and structure-activity relationships of 20S-dammar-24-en-2 alpha,3 beta,12 beta,20-tetrol (GP) derivatives as a new class of AMPK alpha 2 beta 1 gamma 1 activators".BIOORGANIC & MEDICINAL CHEMISTRY 24.12(2016):2688-2696. |
入库方式： OAI收割
来源：上海药物研究所
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