Synthesis And Biological Evaluation Of Novel Aryltriazole Acyclic Nucleoside Analogues

Nucleoside analogues constitute an important class of drugs for treating cancers,viral infections,fungal/bacterial infections and other diseases.However,adverse effects,drug resistance and some other related problems have also generated after the long-term use of these drugs.Therefore,searching for novel nucleoside analogues with high-efficiency and low-toxicity remains an active and appealing area in drug development.Aryltriazole nucleoside analogues have been reported to show various pharmacological activities.The development of novel aryltriazole nucleoside analogues is a promising approach to discover potential drug candidates against various diseases.In this thesis,three classes of novel aryltriazole acyclic nucleoside analogues have been designed and synthesized(Fig.1).Fig.1 The novel aryltriazole acyclic nucleoside analogues designed and synthesized in this thesisThe first class of target compounds are arylethynyl-1,2,4-triazole acyclic nucleosides bearing amino groups(I-IV).The introduction of various amino motifs at the end of the acyclic sugar chain significantly improved the antiproliferation activity of arylethynyl-1,2,4-triazole nucleosides against different cancer cells.Among them,compound II6 displayed most potent antiproliferative activity,which was 6-17 potent than lead compound WMH-116.In addition to the potent in vitro antiprolideration acitivty,compound II6 significantly reduced the tumor volume by 70%in mouse model and did not cause any acute toxicity,highlighting this novel nucleoside analogue with high-efficiency and low-toxicity.Further studies showed that the represented active compound I3f and II6 not noly maintained lead compound's ability to inhibit the heat shock response pathway and induce apoptosis,but also more efficiently caused cell death via autophagy,indicating these novel nucelosides promoted anticancer activity via dual mechanisms of cell death.Moreover,several nucleoside analogues exhibited dual anticancer and antibacterial activities,which represented the first reported aryltriazole nucleoside analogues with such dual biological activities,expanding the potential application of these nucleoside analogues.The second class of target compounds were arylethynyl-1,2,4-triazole acyclic nucleoside-amino acid conjugates(V-VI).Various amino acids were coupled to the acyclic sugar chain of the lead compound WMH-116 through ester bond or amide bond,forming a series of structurally diverse nucleoside-amino acid conjugates.These conjugates having various amino acids exhibited very different antiproliferation activities in cancer cells.The structure&activity relationship analysis showed that the introduction of valine to the 1,2,4-triazole acyclic nucleoside motif could significantly improve the anticancer activity of parent compound.Valine conjugates VIa displayed potent antiproliferative activity,which was 3-14 potent than lead compound WMH-116.The third class of target compounds were aryl-1,2,3-triazole acyclic C-azanucleoside VII,in which the acyclic azasugar was linked to aryl-1,2,3-triazole through C-glycosidic bond.Similar to our previous study,the incorporation of a hydrophobic alkyl chain to the triazole nucleobase of the acyclic azanucleosides had notable impact on their anticancer activity.Compound VIIf bearing a C12 alkyl chain exhibitied the most potent antiproliferative activity.The IC₅₀ value against Panc-1 and Hep G2 was 4.9?M and 4.6?M,respectively.Further studies confirmed that C-azanucleoside VIIf also could inhibit the heat shock response pathway and induce apoptosis.To our knowledge,compound VIIf was the first azanucleoside showed anticancer activity via suppressing the heat shock response pathway.It therefore may serve as a promising lead for exploring azanucleosides as anticancer drug candidates.In summary,we have developed a series of novel aryltriazole nucleoside analogues and evaluated their biological activities.Some active compounds could lead to cell death via carious mechanism resulted in potent anticancer activity.And some active compounds showed dual anticancer and antibacterial activity.These aryltriazole nucleoside analogues with unique structures and mode of action hence constitute promising leads for searching novel anticancer drugs and antibiotics.