The Structural Modification And SARs Studies Of Mogrol As AMPK Activators

Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) is an important cell energy sensor. Once activated by AMPK activators, AMPK can stimulate glucose up take, promote fatty acid oxidation, and inhibit adipogenesis and gluconeogenesis, which is likely to be developped as effective drugs for the prevention and treatment of type 2 diabetes. Our team found that the acid hydrolysis of crude mogrosides exhibited potent activation on AMPK in vitro expiriment. Further study showed that its active ingredientis mogrol, with EC50 of 3.0 μM. Therefore, we selected mogrol as the lead compound andstudied its SARs. Based on our previous research results of protopanoxadiol on AMPK activation, we designed a series of mogrol derivatives, including amine derivatives, amide derivatives, urea derivatives, carbamate derivatives at the 24-position. We firstly oxidized the vicinal diol of mogrol into the aldehyde (mogrol-1), then reductive aminated into amine derivatives (1-22) with different amines; We treated mogrol-1 with I2/NH3·H2O to provide the nitrile (mogroI-4), furtherly reduced into the primary amine (mogroI-2) with LiAlH4. Mogrol-2 was derived into amide derivatives (23-26), carbamate derivatives (30-32) with different acyl chlorides, chloro-carbonic esters, respectively; we treated mogrol-2 with 4-nitrophenyl chloroformate to provide the active carbamate intermediates (mogroI-5), then furtherly derived urea derivatives with different amines (27-29). The targeted compounds (1-32) and mogrol intermidates (1-4) were evaluated on the activation of AMPKa2plyl, and compounds 3,15,18,21,22 mogrol-3 and mogrol-4 enhanced the activation of AMPK heterotrimer with EC50 0.15μM, 0.2μM,0.5μM,0.5μM,0.7μM,1.0μM and 0.5μM, respectively, the most potent compond 3 was 20 times more potent than the parent compound mogrol.Among them, the most potent compounds (3 and 15) inpotency (EC50:0.15 and 0.20μM) were selected for further investigation.