Study On Synthesis And Antitumor Activity Of 1'-alkyl Substituted Acyclic Nucleosides

At present,the malignant tumor is the deadly disease that seriously impact on human life and health,the development of anticancer drugs has been an important research direction of innovative medicines.Because of the similar structure with natural nucleosides in different degree,nucleoside analogues play an important role in antitumor and antiviral,thus its chemical synthesis and pharmacological activity research have always been the focus in medicine.In nucleoside compounds,acyclic nucleoside drugs develop rapidly in recent years,which have now became the research emphasis of a new generation antitumor nucleoside drugs.The research on acyclic nucleoside compounds mainly concentrated on the synthesis and antiviral activities,however,the research on its antitumor activity is few.In order to enrich the research on the application of acyclic nucleoside compounds,and based on the research of our group,we designed a series of novel 1' substituted acyclic nucleosides,to study the antitumor activity and then summarize the structure-activity relationship.This paper is mainly including the following three parts:1.The synthesis study of novel acyclic nucleoside compoundsWe synthesized a series of 1'-substituted acyclic nucleoside compounds through the Aza-Michael addition reaction,and on the basis of these compounds,conversion of the 2,6-functional groups,then screened out several active ones from these compounds,synthesized the corresponding R and S conformations of chiral compounds.The structure of the novel acyclic nucleoside compounds have been determined by characterization of the structure,including 1H NMR,13 C NMR,and the single-crystal structure.2.The antitumor and structure-activity relationship study of novel acyclic nucleoside compoundsThe 25 kinds of synthesized acyclic nucleoside compounds were determined by MTT method to test the inhibition of Hela(human cervical cancer cells),PC-3(human prostate cancer cells),A549(lung cancer cells),HCT116(human colon cancer cells),SK-hep-1(human liver cancer cells)and SK-OV-3(human ovarian cancer cells)proliferation,and the cytotoxicity of 293T(human embryonic kidney cells)and 3T3(mouse embryonic cells).Through the analysis of the test data,summarized the 2-,6-,1'-substituted structure-activity relationship of the purine acyclic nucleosides,in these compounds,the half inhibitory concentration IC50 of the compound 9a can reach about 2 ?M,the inhibition activity is better than the antitumor drugs 5-fluorouracil(5-FU),and lower toxicity,provided the research basis for seeking better antitumor prodrugs.3.The synthesis study of 3-cyanomethyl oxoindoles3-Cyanomethyl oxoindoles are a kind of important drug intermediates,which can be used to synthesize horsfiline,esermethole and physostigmine and other natural products via the conversion of cyano functional groups.In this paper,we use water as solvent,synthesized a series of oxoindole compounds through the domino Heck/cyanation reaction,which have been determined by characterization of the structure,including 1H NMR,13 C NMR,HRMS.Compared with the traditional method,this method use green environmental medium water instead of harmful organic solvents,without any basic additives,and easy to operate,provided a green and efficient new procedure for the synthesis of 3-cyanomethyl oxoindoles.At the same time,the reaction can still maintaining high yield in a large number of tests,probably for industrialized production.