Construction Of The Structural-diversity Small Molecular Covalent Inhibitor Library And The Study Of Its Bioactivity Against Osteosarcoma

Osteosarcoma is a malignant tumor that derived from mesenchymal bone.It is the most common malignant tumor in the skeletal system and is prone to relapse and metastasis.It often occurs in young people under the age of 20.At present,the most common treatment methods are chemotherapy and radiotherapy,but these two treatment methods are very harmful to patients,and the survival rate within 5 years is not high;although emerging gene therapy and immunotherapy bring new hope,they are effective Sex and safety are uncertain.Although the emergence of molecular targeted therapy has pointed out a new direction for the treatment of tumors,most of the existing small molecule targeted drugs are non-covalent bond inhibitors,and they are not developed for osteosarcoma targets.They have limited effectiveness and still exist.With poor selectivity and other defects.In addition,due to numerous subtypes of osteosarcoma,complicated pathogenesis,unclear targets,and fewer targeted drugs for existing targeted therapies,the development of new small molecule covalent bond inhibitors to treat osteosarcoma is already urgent.Small molecule covalent bond inhibitors are a class of drugs that bind to specific target proteins through covalent bonds.Compared with traditional non-covalent inhibitors,covalent bond inhibitors have high selectivity,high efficiency,and relatively long action time.Especially for some tumors with unclear targets,it has unique advantages.These advantages of covalent bond inhibitors can solve the problems faced by molecular targeted therapy of osteosarcoma.With the improvement of drug screening technology,the compound libraries obtained by traditional synthetic methods have been difficult to meet the needs of modern drug development.The diversity-oriented synthesis strategy can quickly and efficiently build a compound library of structural diversity.Based on this strategy and the threecomponent reaction of mature carbene,this article introduces some of the most common electrophilic warhead units / heterocyclic fragments into the three-component reaction substrate,initially explored the feasibility of its reaction,and successfully introduced the pyridine ring It is introduced into the substrate diazo to obtain the target threecomponent product;secondly,the warhead unit of acrylamide group is introduced into the insertion reaction of diazo and aromatic amine,and a series of active compounds are successfully obtained through subsequent derivatization.The first chapter introduces osteosarcoma and some of its existing treatments and drugs,the mechanism of action and advantages and disadvantages of small molecule covalent bond inhibitors,the construction strategy of structural diversity compound library and the overall research strategy of this article.In the second chapter,we successfully introduced common electrophilic warhead units,such as acrylamide,N-methacrylamide,propionamide,ethynyl and maleimide,into methyl phenylacetate diazo.In the insertion reaction with aromatic amines,a series ofα-amino ester compounds were prepared.Afterwards,we designed a series of α-amino-β-hydroxy compounds,oxazolidinones and oxazolidine thione compounds containing electrophilic warhead units based on the insertion reaction of diazo and aromatic amines These compounds were synthesized and a library of covalent bond inhibitors with structural diversity was constructed.This result laid a solid foundation for the subsequent introduction of electrophilic warhead units into the three-component reaction.In the third chapter,we continue to introduce acrylamide into the second component of nucleophilic reagents and conduct preliminary screening of the reaction conditions and reagents.Some reactions have been able to observe the target three-component products.This result fully illustrates the feasibility of introducing acrylamide groups into the three-component reaction.In the fourth chapter,we then introduced electrophilic warhead units such as propynamide,maleimide and ethynyl into the three-component reaction,and further explored the feasibility of the reaction.Both the introduction of the maleimide group into the imine and the introduction of the ethynyl group into the second-component nucleophile are sufficient to observe the target three-component product.This shows that it is also feasible to introduce electrophilic warhead units other than acrylamide groups into the three-component reaction,which explains the introduction of covalent bond warhead units into the three-component reaction and the development and construction of structurally diverse covalent bonds The inhibitor library is feasible.In the fifth chapter,we introduced some heterocyclic electrophilic warhead units into the three-component reaction system and made a series of explorations.Finally,we successfully introduced pyridine heterocycles from diazo to obtain the desired threecomponent products.The optimization of the subsequent conditions of the reaction and the asymmetry attempts are still in progress.In the sixth chapter,we conducted a preliminary anti-bone for the α-amino ester compounds,α-amino-β-hydroxy compounds,oxazolidinone and oxazolidine thione compounds prepared in the second chapter Tumor biological activity screening.The research results show that most of the compounds have a good inhibitory effect on osteosarcoma.In addition,we also tested the reactive oxygen photoelectric reaction of the compounds II-9a and II-9b,these two compounds can quickly cause cell stress response.The eighth chapter is the experimental part.