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
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
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作为一类新的 AMPK α 2 beta 1 gamma 1 激活剂的 20S-dammar-24-en-2 α,3 beta,12 beta,20-tetrol (GP) 衍生物的发现、合成和构效关系
DOI：
10.1016/j.bmc.2016.04.034
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发表时间：
2016
影响因子：
3.5
通讯作者：
Hu Lihong
中科院分区：
文献类型：
--
作者：
Dong Chenhuan;Xie Zhifu;Yu Yanyan;Li Jia;Liu Junhua;Li Jingya;Hu Lihong
20 S-dammar-24-en-2α，3 β，12 β，20-tetrol（GP，1）是一种达玛烷型三萜类化合物，对金黄地鼠血脂异常有一定的代谢作用，在分子水平上激活AMPKα2β1γ1约2.4倍，EC_（50）为5.1 μM。为了提高其对AMPK的活性和构效关系的研究，我们设计、合成了GP衍生物，并在药理学AMPK活化试验中对其进行了评价。构效关系分析表明，在24位的胺（组I-IV）有效地和显着增加的效力和功效。GP衍生物12和17 - 19在激活AMPK异源三聚体α2β1γ1方面表现出比阳性对照（AMP，EC 50：1.6 μM，倍数：3.2）更好的效力（EC 50：0.3、0.8、0.8和1.0 μM）和功效（倍数：3.2、2.7、3.0和2.8）。此外，最有效的化合物12和17通过增加AMPK的磷酸化而明显抑制葡萄糖输出，而不影响线粒体膜电位或产生细胞毒性。
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 EC50of 5.1 μM 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 derivatives12and17–19exhibited better potency (EC50: 0.3, 0.8, 0.8, and 1.0 μM) and efficacy (fold: 3.2, 2.7, 3.0, and 2.8) in the activation of AMPK heterotrimer α2β1γ1 than positive control (AMP, EC50: 1.6 μM, fold: 3.2). Furthermore, the most potent compounds12and17obviously inhibited glucose output through increasing the phosphorylation of AMPK, without affecting mitochondrial membrane potential or producing cytotoxicity.