Synthesis Of Novel 1,2,4-Triazole Nucleosides And Evaluation Of Their Biological Activity

Synthetic nucleoside drugs are an important class of anticancer and antiviral drugs. They are able to mimic natural nucleosides and serve as building units or inhibitors to interfere in nucleic acid synthesis or block nucleoside(tide)-dependent biological process, leading to inhibition on viral replication and cancer cell proliferation, and consequently potent and effective antiviral and anticancer activity. Ribavirin and Gemcitabine are two examples of nucleoside antiviral and anticancer drugs against HCV infection and pancreatic cancer, respectively (Figure 1). Many anticancer and antiviral drugs are obtained based on the modification of natural nucleosides. Recently, introducing various aromatic functionalities to the nucleobase has generated some promising active nucleosides, such as HEPT and 6-arylpurine (Figure 1), which exhibit potent and selective anti-HIV-1 and apoptosis-activity, respectively.Our group is working actively on developing triazole nucleoside analogues bearing various aromatic moieties, some of them demonstrated excellent antiviral and anticancer activity. Based on our previous work, we would like to further develop the triazole nucleoside compounds containing aromatic moieties introduced on the triazole ring via either a triple bond (A in Figure 2) or a triazole ring bridge (B1 and B2 in Figure 2). We expected that by appending aromatic system onto triazole nucleobase may improve interaction between nucleosides and biological targets, resulting in more potent compounds with anticancer and antiviral activity. Furthermore, as CN functionality has been discovered in many clinical drugs as pharmacophore by virtue of its short, polarized and hydrogen-bond receptor triple bond, we would like to create triazole nucleosides bearing CN onto the triazole ring. In my thesis, I firstly synthesized triazole nucleoside A bearing various heterocyclic moieties on the triazole ring via Sonogashira cross coupling reaction using bromotriazole nucleosides as substrates (Figure 3). I then constructed bitriazolyl nucleosides B1 and B2 via Huisgen reaction starting with triazole nucleosides containing internal alkynes and terminal alkynes, respectively (Figure 4). Finally,I prepared various triazole nucleosides with nitrile group attached onto the triazole ring (Figure 5). All the synthesized triazole nucleoside analogues were assessed for antiviral and anticancer activity using HCV、TMV、pancreatic cancer and prostate cancer as antiviral and anticancer models, respectively. Some of them showed interesting anticancer and antiviral activity. Among the active leads, compounds 3-6,5-9 and 6-4a exhibited the most promising anticancer activity against drug-resistant pancreatic, with potency much better than the clinical drug Gemcitabine. SAR studies were undertaken based on 3-6,5-9 and 6-4a, and further investigation on the anticancer mechanisms of 3-6 and 5-9 are currently underway.