Synthesis And Pharmacological Activity Studies Of Some Eudesmane Nature Products And Their Derivatives

The natural product (+)-Carainterol A was reported to have potent hypoglycemic effect. (+)-Carainterol A embodies a different structure from the existing anti-diabetic drugs. However the mechanism of its pharmacological effect remains unknown. Therefore, (+)-Carainterol A could be used as a molecular probe to investigate the mechanism of hypoglycemic action. In this paper, we figure out a scheme for asymmetric total synthesis of (+)-Carainterol A. In the synthetic route, we employed the effect of the existing structure on asymmetrically introducing the functional groups in synthetic reactions. Eventually we completed the synthesis of (+)-Carainterol A in 12 linear steps with the 4.5% overall yield. The spectrum of synthetic (+)-Carainterol A is consistent with the genuine natural product. In the course of this research, we totally synthesized 16 compounds, of which 13 compounds are new compounds. On the basis of this synthetic route, we carried out the modification of (+)-Carainterol A in order to get more active compounds. We fulfilled the synthesis of a series of 7-substituted derivatives and 25 compounds had been synthesized, of which 20 compounds are new compounds. The preliminary data of biological test of the derivatives and some intermediates indicated that the compounds couldincrease theglucose transportactivity at 5μM which was superior to the lead compound. In order to demonstrate the flexibility and applicability of the (+)-Carainterol A synthetic route, we choose to apply it to the synthesis of the natural product Y019 which showsanti-Pyriculariaoryzae P-2b activity. Finally we completed the total synthesis of Y019 in 11 linear steps with 9.4% overall yield. In the research process, we accomplished the synthesis of 12compounds, of which 7 compounds are new compounds. We also tried to employ virtual reverse docking and molecular biology methods to explore the mechanism and the exact targets of (+)-Carainterol A. The experimental results indicated that the target of (+)-Carainterol A is different from the existing targets of anti-diabetic drugs and (+)-Carainterol A can concentration-dependently increase the IRS-1 protein level in the insulin signaling pathway. However, the exact target has not been identified.In this paper, we also designed and synthesized a series of HIV integrase inhibitors embodying pyrrolidone structure. After analysis of the structure of known HIV integrase inhibitor, we established a pharmacophore model and screened the in-house compound library.22 hit were selected for synthesis and pharmacological activity test. The results showed that the IC5o of three compounds reached 40μM and was superior to the lead compound. We also received a preliminary structure-activity relationship that is useful for further structural modification.