Preparation And Biological Evaluation Of Novel Nucleoside Analogues

Nucleoside analogues have been adopted as antiviral and antitumor agent for many years. Zidovudine (AZT), a 2’-deoxy-3’-azido-thymidine was first approved by the FDA to treat patients with HIV. Another analogue: Lamivudine was the first nucleoside to treat chronic Hepatitis B. Even though the antiviral and antitumor nucleosides had placed such important role in treatment of viral disease, there are still side-effects or resistance that counterworks the application and development of nucleoside drugs. To break through these bottlenecks, medicinal chemists focus their attention on design and synthesis of more and more novel nucleoside analogues with high efficacy and low toxicity.The antiviral and antitumor mechanisms of nucleosides are:①they can be introduced into the DNA/RNA replication chain by mimicking natural ones, but these analogues would terminate the chain extension, because of their chemical differences.②They competitively inhibit the DNA/RNA polymerase so that natural nucleotides cannot be polymerized to form the DNA/RNA chain.Based on previous research data, we mainly discuss in this thesis, the design and synthesis of novel nucleoside analogues with carbohydrate fraction modified. Starting from natural ribonucleosides, we successfully produced a series of sugar and base fragment modified L-nucleoside enantiomers, and fluorinated or azido substituted seconucleosides. The synthetic route went through following steps: selective protection of major hydroxyl and amido groups; oxidation and bond breaking of 2’,3’-carbons; tosylation on 2’,3’-hydroxyl; then nucleophilic substitution at 2’,3’-carbons to result in azido and fluoridation substitution seconucleosides or to form a six-membered ring via cyclization; finally: deprotection. 19 compounds were prepared successfully and characterized by 1H NMR, 13C NMR or MS.The results of biological tests concerning antitumor and antiviral activity indicated that 2’,3’-seconucleosides with diazido-substitution on 2’,3’-position are less active than 2’-azido, 3’-fluorinated ones in anti-HSV-I test. It shows that fluorine atom on 3’-position plays important role for the antiviral effect. Meanwhile, the diazido acyclic nucleosides show no antitumor effect on T47D and NCI-H460 cells. In both vero cells and tumor cells, the compounds showed no cytotoxicity.