(1)Synthesis Process Optimization Of Betrixaban And Design,Synthesis And Biological Evaluation Of Betrixaban Derivatives;(2)Discovery Of Arylthioacetanilides As Anticancer Lead Compounds

Cardiovascular and cerebrovascular diseases and malignant tumors seriously endanger the life and health of all human beings.Among them,the main cause of cardiovascular and cerebrovascular diseases is the abnormal formation of thrombosis,including deep vein thrombosis,stroke,myocardial infarction and so on.The occurrence of malignant tumor is closely related to smoking,infection,occupational exposure,environmental pollution,unreasonable diet,heredity and other factors.Although there are many antithrombotic and tumor drugs in clinical application,there are still some shortcomings such as poor patient compliance,drug resistance,narrow treatment window and poor drug selectivity.Therefore,the development of effective and safe antithrombotic and tumor drugs is still a hot spot for new drug research in recent years.Abnormalities in the coagulation system are the leading cause of thromboembolic disease,and there are two coagulation pathways in human body which are Extrinsic coagulation pathway and Intrinsic coagulation pathway.FXa is an important protein which link the two coagulation pathways,and play a key role in the process of blood clotting and thrombosis.Therefore,FXa has become a hot target in the development of antithrombotic drugs in recent years.Betrixaban(PRT054021)is a novel oral direct FXa inhibitor developed by portola pharmaceutical company.It is widely used in the prevention and treatment of venous thromboembolism in clinic,and Betrixaban has advantages of high selectivity and low hepatorenal toxicity.However,the synthetic route of betrixaban which reported in the literature has defects such as complex synthetic operation,high cost and low yield.In the first part of this paper,by changing reaction temperature,reaction solvent and post-treatment steps,the intermediate synthesis route is optimized,the reaction time is shortened,the production cost was reduced,and the overall yield of the route is improved(59.5%-65.3%),The synthesis route is more in line with the requirements of green chemistry and more suitable for industrial production.The second part of this paper,we use betrixaban as a lead compound and designed three series of derivatives.The P4 and Linker regions of the lead compound were modified via using the bioisosteric and the molecular hybridization strategies.In addition,we used computer-aided drug design to simulate the binding mode of the designed compounds,and the scoring results showed that the designs of three series of compounds were theoretically reasonable.The 22 target compounds were synthesized by acylation reactions,reduction reactions and click reactions,and the structures of those sulfonamides and amide derivatives were confirmed by spectroscopy.In this paper,FXa inhibitory activity at protein level and prothrombin prolongation time of target compounds 1-12 were tested.The inhibition rate of IC50 and prothrombin time of FXa by betrixaban were calculated.The results showed that the compound 10 had weak activity,while the other compounds showed no inhibition activity.It is possible that sulfonamide groups were not suitable for the binding requirements.Tumor is a new organism formed by local tissue cell proliferation under the action of various tumorigenic factors.Malignant tumors are characterized by disordered cell cycle,rapid cell proliferation and division,and strong invasiveness.Theoretically,any cycle of tumor cell activity can be used as a target for anti-tumor drug development,but how to develop an effective and highly selective inhibitor is still a difficult problem for anti-tumor drug development.After literature research,we found that heterocyclic glycosamides have a wide range of biological activities,and they can be used as the basic structure of pharmacophore parent nuclei to meet the space requirements of specific drug targets.It can also be used as an active substituent or a part of a ring system to produce the corresponding biological activity.In addition,these compounds have good properties of drug like properties and biocompatibility.The third part of paper,the anti-tumor activity of arylthioacetanilides was tested on the basis of the existing arylthioacetanilides in our research group,and three relatively active compounds were obtained.In summary,this paper not only makes a systematic optimization of the synthesis process of betrixaban,and discusses the systematic conditions for the industrial production,but also tested a series of and the activity of heterocyclic glycosamides derivatives.In addition,a series of betrixaban derivatives were synthesized,some compounds was preliminarily screened,but the activity was far from that of the lead compounds,which has accumulated experience for the discovery of efficient FXa inhibitors in the future.