Study On Synthesis And Structure-activity Relationship Of Antidiabetic 5,7-dihydroxy Flavonoids Derivantives

Objective Tiliroside was the main anti-diabetic constituent isolated from Potentilla chinensis Ser. The preliminary pharmacokinetics research on tiliroside showed that the compound was quickly metabolized into cinnamylic acid,kaemferol-3-O-β-D-glucoside and kaemferol in vivo. We speculated that kaemferol with 5,7-dihydroxy flavone was the effective structural segment of tiliroside. Two series of 5,7-dihydroxy flavonoids were synthesized and the structure-activity relationship for antidiabetic effects was investigaited. The result will provide valuable information for further structure optimization and discovery of candidate new drugs.Methods 1. Synthesis of derivatives: the derivatives were synthesized on four routes.All the compounds were identified by spectroscopic methods.2. Evaluation of the anti-diabetic activity of the derivatives: all the derivatives were investgated for the glucose consumption of the insulin resistance HepG2 cells with the glucose oxidase method. Median Effective Concentrations(EC50) of the positive control and the derivatives were calculated. Anti-diabetic activities and structure-activity relationship of the derivatives were evaluated.3. Moleculer docking: the possible target of all the derivatives was analyzed with the moleculer docking.Results 1. Seventeen compounds, including eight 5,7-dihydroxy flavanones and nine 5,7-dihydroxy flavones were synthesized by medicinal chemistry methods. The structures of the derivatives were identified with spectroscopic methods. Compounds A7、B1 and B4 were new compounds.2. All of the derivatives could improve the glucose consumption of the insulin resistance HepG2 cell except B5. Compounds A2, A5, A7 and B8 revealed significant activities compared with that of market drug, Metformin, and compouds A6, B4 and B9 showed stronger activities than Metformin.3. The docking results showed that anti-diabetic compounds could be well docked with PEPCK. Compounds A6, A7, A8 and B1 got high scores. The result mostly corresponded with that of the anti-diabetic activity experiment.Conclusion Aiming to study the structural elements essential to the antidiabetic flavonoids, we synthesized 17 5,7-dihydroxy flavonoids including three new compounds. In a screening of in vitro antidiabetic activity experiment, most of the flavonoids showed a remarkable in vitro activity, and compounds A6、B4 and B9 were significantly more effective than the positive control, Metformin. The biological activity was mainly affected by introducing structural modification at the ring B moiety of the flavonoid skeleton. The activity would be lower after the hydroxy group was removed but stronger when the ring B became to a five-membered ring especial a furan ring. With the same ring B, flavanone analogues have better antidiabetic activity than flavone analogues, which maybe relates to the flexible changes happened on the space of ring C. The molecular docking results showed that the hydroxy of the compounds may form hydrogen bonding interaction with the target, which was the main group combined with the target. Three rings of flavonoid skeleton could have hydrophobic effect with the target. The docking results mostly corresponded with the resoult of the anti-diabetic activity experiment. Therefore, it can be argued that the derivatives may play antidiabetic effects via PEPCK.