Structure Modification And SARs Study Of Two Abundant Triterpenoids On Activation Of AMPK Phosphorylation

This thesis consists of two parts:(1) structural modification and SARs study of 2α-OH protopanoxadiol(GP) as AMPK activators;(2) structural modification and SARs study of Hemslecin A(XD) as AMPK activators.Adenosine 5 ’- monophosphate- activated protein kinase(AMPK) plays a vital role in regulating glucolipid metabolism and energy balance at both cellular and whole-body level. Therefore, AMPK has become a promising target in the fields such as obesity and type 2 diabetes.Gynostemma yixingense is honoured as the "Southern ginseng", drugs consisted of Gynostemma total saponin are preferred for the prevention and treatment of senile hyperlipidemia. Howerer, its effective component and mechanism are still unclear. Our previous study found 2α-OH protopanoxadiol(GP), the aglycone of Gynostemma yixingense, could not only activate the restructuring anthropogenic AMPKα2?1?1 with EC50: 5.1 μM at molecular level, but also showed good lipid-lowering activity in mice. Besides, the C-24, 25 double bond of GP experinced oxidative metabolism. Therefore, in order to explore the importance of the double bond, study the SARs of GP as AMPK activators, and clarify the mechanism of glucolipid metabolism, we designed and synthesized 20 derivatives including the metabolites, and evaluated their activity on AMPK. As a result, GP derivatives 12, 17, 18 and 19 exhibited better potency(EC50: 0.3, 0.8, 0.8 and 1.0 μM) than the positive control AMP(EC50: 1.4 μM). Furthermore, the most potent compounds 12 and 17 obviously inhibited glucose output through increasing the phosphorylation of AMPK, without affecting mitochondrial membrance potential or producing cytotoxicity.Hemsleya amabilis Diels has been widely used in China for its anti-bacterial, anti-inflammation and liver protection activity. We found that Hemslecin A(XD), the most abundant components of Hemsleya amabilis Diels, exhibited good activation on AMPKα2?1?1 with EC50: 8.3 μM by structure similarity searching and activity screening. In order to enhance its potency on AMPK, 14 XD derivatives were designed, synthesized and evaluated. As a result, XD-4、XD-8 and XD-12 showed most potent activity(EC50: 1.7, 1.8 and 0.6 μM), among which, XD-12 improved nearly 15 times than the lead compound. On primary hepatocytes, XD-4 obviously inhibited glucose output.Our work not only provides a useful reference for fully developing and utilizing the hypoglycemic and lipid-lowering efficacy of Gynostemma yixingense and Hemsleya amabilis Diels, but also lays a good foundation for exploring and discovering new triterpenoids with AMPK phosphorylation activity from the treasure house of Chinese herbal medicine resources.