Synthesis And Antitumor Study Of Novel Bitriazolyl Nucleoside Analogue

Nucleoside analogues are compounds obtained by chemical modification of natural nucleosides.They can mimic the structure and mechanism of natural nucleosides and inhibit cancer cell proliferation and viral replication by interfering with the synthesis of DNA and RNA,and finally achieving the antitumor or antiviral effect.The bitriazolyl nucleoside analogues are a family of bioactive lead compounds,which can not only effectively inhibit the proliferation of tumor cells,but also regulate the immune response in the biological system.Dimethylamino and nitrile groups are common functional groups in pharmaceutical molecules.The introduction of dimethylamino group into the pharmaceutical molecules can effectively improve the physicochemical properties of the drug,increase the interaction between the compounds and the target proteins,and improve the metabolic properties of the drug etc.Nitrile group is a functional group containing C-N triple bond,which can interact with the residues of key amino acids or behave as bioisosteres of carbonyl,halogen etc.Therefore,nitrile group can improve the pharmacological properties of small molecules by enhancing the interaction between the molecules and the target protein resulted in improved bioactivity.Moreover,nitrile group can act as a metabolic blocking point to prevent the oxidative metabolism of small molecules hence to improve the metabolic stability of the compounds in vivo.Therefore in this thesis,we designed two kinds of bitriazolyl nucleoside analogues,one of which has dimethylamine group on the terminal of glycosyl aiming to improve the cell uptake and the bioavailability of the compounds.The another ones contain the nitrile group on the 1,2,4-triazole base with the aim to improve the antitumor activity of the parent compounds.The bitriazolyl nucleoside analogues bearing dimethylamino group and nitrile group in sugar moiety and base part,respectively,have been synthesized and their antitumor activity were assessed in various cancer cell in vitro.The antiproliferation activity of these compounds was tested by MTT test,and several lead compounds were screened out.The structure and activity relationship analysis confirmed that the introduction of dimethylamino and nitrile group could enhance the antiproliferation activity of parent molecules.We further studied the mechanism of action of these bitriazolyl nucleoside analogues for their anticancer activity.The results showed that both series of compounds could inhibit the proliferation of tumor cells via inducing apoptosis.At the same time,the expression of heat shock factor-1(HSF1),heat shock protein 27(HSP27)and its client protein eIF4 E were down-regulated by the lead compounds.Hence,this family of compounds may have good potential against drug-resistant tumor cells with overexpression of heat shock proteins.In conclusion,we have designed and synthesized two types of novel bitriazolyl nucleoside analogues.The introduction of dimethylamino group and nitrile group into the parent nucleoside compounds effectively improves their antitumor activity,which open new perspect to develop novel nucleoside drugs to treat cancer and other life-threatening diseases.