Design And Synthesis Of Anti-osteosarcoma Small Molecule Drug Probes

Small molecule drug probes are powerful tools for drug target discovery and discovery of new active molecules.In the case of retaining a reactive group of a drug molecule,a specific reporter group or the like is introduced by modification,and the designed molecule not only has a biological activity similar to that of a drug molecule,but also provides a molecular mass by chemical biological means.Information on the interaction between the active molecule and the target protein for target discovery,confirmatory studies,or direct drug discovery.Design and synthesis of an effective,ideal drug molecular probe,two key prerequisites: 1.After modification,the activity of the probe molecule can be maintained;2.There are chemical sites for modification,even multi-site modification.However,in actual research,due to the limitation of chemical synthesis,not all active molecules or drug molecules can effectively obtain the corresponding probe molecules.For some major diseases whose current target is not clear,the development of new and effective drug probe molecules for target discovery and confirmation research is of great significance for the development of targeted drugs.Osteosarcoma is a common malignant tumor in adolescents with a very poor prognosis.The current common treatments are chemotherapy and radiotherapy,but it is extremely harmful to patients,and the 5-year survival rate is not high.New gene therapy and immunotherapy bring new Hope,but there are high risks due to individual differences.Since the current target of osteosarcoma is not clear,especially for metastatic osteosarcoma,there is no corresponding molecular targeted drug development.Therefore,the development of a small molecular probe against osteosarcoma,the discovery and confirmation of potential targets,has important guiding significance and practical application value for the development of such targeted research.The first chapter of the thesis introduces the target discovery technology based on chemical biology,affinity chromatography and activity-based protein profiling technology,and discusses the small molecule probe technology and its classification,as well as the design ideas of this paper.In the second chapter of the paper,we further studied the three-component reaction product of the substrate imine without phenolic hydroxyl group on human osteosarcoma SJSA-1 based on previous studies on the activity of α,β-diamino acid ester and its derivatives.The inhibitory activity of the cells was summarized based on the obtained activity data,and the feasibility of active site and multi-site modification was determined.In the third chapter of the thesis,based on the structure-activity relationship of α,β-diamino acid esters and their derivatives,we designed several small molecular probes directly linked to reporter groups(including Biotin and rhodamine)to construct Molecular probe libraries,and the molecular activity of these probes were maintained,optimizing the click reaction conditions of these compounds,which laid the foundation for the screening of reaction conditions for the capture of proteins in cell lysates.We have also designed linking groups with different chain lengths to study the selective effects of the linking groups on the probe molecules.The fourth chapter of the thesis is the experimental part.Based on the phenotypic screening of active compounds containing α,β-diamino acid ester derivatives containing acetylenic acid groups,a series of novel small molecule probes were designed and synthesized by structure-activity relationship.The feasibility of chemical synthesis of site-modified probe molecules lays a foundation for anti-osteosarcoma drug probe molecules,target confirmation and drug discovery.