Design, Synthesis And Biological Evaluation Of 1,2,4-Triazole Nucleoside Derivatives

Nucleoside analogs are important candidates in the searching of antiviral and anticancer drugs. The nucleoside drugs can mimic natural nucleosides and as such serve as building units or inhibitors that interfere in nucleic acid synthesis or block nucleos(t)ide-dependent biological processes, thus leading to potent and effective antiviral and anticancer activity, respectively.Based on the previous work related on the synthesis and biological assessment of 1,2,4-triazole nucleosides analogs developed in our laboratory, we have further designed four types of novel aryltriazole nucleoside analogues (Figure 1). They bear arylamino, arylthio/alkylthio and arylethynyl/alkylethynyl on the triazole nucleobase respectively, with the aim to develop novel triazole nucleoside analogues with potent antiviral and anticancer activity.These triazole nucleosides were synthesized using N-arylation, S-arylation and Sonogashira reaction (Figure 2). The obtained compounds were assessed of their antiviral activity against HCV, anticancer activity against human pancreatic cancer and human prostate cancer. Two N-aryltriazole nucleosides (Figure 3, A-02 and A-14) showed interesting inhibitory activity on cell growth of drug-resistant pancreatic cancer MiaPaCa-2 cells, with a better potency than the clinical drug gemcitabine, whereas two other arylethyltriazole nucleosides (Figure 3, H-01 and H-02) displayed significantly inhibition on pancreatic cancer MiaPaCa-2 cells and prostate cancer PC-3 cells, with much better potency than the clinical drug gemcitabine and taxol, respectively. In addition, both H-01 and H-02 showed novel mechanism of action by down-regulation of heat short protein 27 (Hsp27), which is completely different from that of gemcitabine. All these findings collectively demonstrate that aryltriazole nucleosides are promising candidates in searching for novel antiviral and anticancer agents with new modes of action.