Synthesis And Anticancer Study Of Novel 1,2,4-triazole Acyclic Nucleosides Analogues

Synthetic nucleoside analogs can mimic the natural nucleosides and interfere in nucleic acid synthesis or block nucleoside（tide）-dependent biological process,leading to the inhibition of cancer cell proliferation and viral replication.Currently,nucleoside analogues have been widely used in clinic thanks to their potent biological activities against cancer,virus and fungal/bacterial infection,in which ribavirin,acyclovir and gemcitabine are well-known drugs for antiviral and anticancer treatment.The modifications on the base and/or sugar moiety of nucleosides are the major ways to create novel nucleoside analogues.1,2,4-triazole analogs are an important family of bioactive molecules with diverse pharmacological activities,such as anticancer,antiviral,antibacterial and antipsychotic activities etc.This is because as hydrogen bond acceptor or donor,1,2,4-triazole can efficiently interact with its biological targets in vivo.In the past years,the aryl 1,2,4-triazole nucleoside analogs have been reported to exhibit very promising anticancer and antiviral activities.In this thesis,two types of novel 1,2,4-triazole acyclic nucleoside analogues were designed and synthesized.One is3-arylethynyl-1,2,4-triazole acyclic nucleosides,which is designed to discover novel drug candidates as well as for structure-activity relationship analysis;Another type of molecues is developed via replacing the hydoxyl by dimethylamino group on the acyclic glycosyl of 3-arylethynyl-1,2,4-triazole acyclic nucleosides,aiming to increase the cell permeability hence to improve its biological activity.The synthesis of 3-arylethynyl-1,2,4-triazole acyclic nucleoside was performed via Sonogashira reaction employing 3-iodo-1-[（2-hydroxyethoxy）methyl]-1,2,4-triazole-5-carboxamide rather than its bromo counterpart,which significantly improved the reaction yield and afforded broader substrate scope.The fruther introduction of dimethylamino group to the acyclic glycosyl moiety led to the dimethylamino derivaties of 3-arylethynyl-1,2,4-triazole acyclic nucleoside.These obtained target compounds have been characterized by ¹H NMR,¹³C NMR,IR and MS.Then we assessed the antiproliferation activity of the synthesized compounds on a variety of cancer cells.Some of the 3-arylethynyl-1,2,4-triazole acyclic nucleosides exhibited potent antiproliferation activity.Meanwhile,their dimethylamino analogues displayed even better activity to fight against cancer.Our further studies showed that these compounds can induce apoptosis by inhibiting the expression of proteins involving in heat shock response pathway,and does not cause cell membrane rupture and destruction.In summary,we have successfully developed a series of novel1,2,4-triazole acyclic nucleoside analogs with potent anticancer activity.The promising bioactivity,novel anticancer mechanism of action and lower toxicity to normal cells of these 1,2,4-triazole acyclic nucleosides have highlighted their clinical potential as chemotherapeutic agents to treat cancer and other life-threatening diseases.