Molecular Design And Synthesis Of Novel Nucleoside Analogues

Nucleoside drugs play an important role in the treatment of viral diseases. Atpresent, the proportion of nucleoside compounds used in clinical as antiviral drugsaccounted for more than60%. Side effects and drug-resistance continued to be acommon problem with the antiviral chemotherapeutic agents; therefore, thedevelopment of new antiviral drugs has not only theoretical significance, but alsopractical needs.We firstly introduced related background, systematically reviewed anti-virusnucleoside inhibitors and its clinical use, and analyzed the structure of inhibitors. Sixseries of novel nucleoside virus inhibitors were designed and their bioactivities wereevaluated by molecular docking. The formation of triazole group was a key step, sixseries of novel nucleoside analogs were synthesized by our effective synthetic routes.In Chapter2, a series of N-hydroxyl-1,2,3-triazole nucleoside analogues andN-vinyl-1,2,3-triazole nucleoside analogues were designed and synthesized. Startingfrom2-butyne-1,4-diol and benzoic acid2-azide ethyl ester, we have successfullyaccomplished the synthesis of a series of N-hydroxyl-1,2,3-triazole nucleosideanalogues in10steps in overall yield (0.9%-1.8%). The1,2,3-triazole ring waseffectively constructed via Huisgen1,3-dipolar cycloaddtion and the hydroxyl groupwas selectively protected by different protecting group. In the presence of amine andsodium methoxide,6-cholro of purine was substituted by relative nucleophile;meanwhile, the benzoyl group was removed in one step. We found that N-ethylmesylate reacted with TBAF can not to produce fluoro compound, but to yieldN-vinyl compounds via elimination. p-TsOH as the catalyst in the acetonitrile andwater was the optimal condition for removing TBDMS group. The absoluteconfiguration of2.9a was determined by X-ray analysis.In Chapter3, a series of fluoroethyl-1,2,3-triaozle nucleoside analogues weredesigned and synthesized. Using4-O-trityl-2-butyn-1-ol and2-fluoro ethyl azide asstarting materials, triazole mixture derivatives3.6a and3.6b were synthesized viaHuisgen1,3-dipolar cycloaddtion. The mixture was separated by chromatography andthe absolute configuration of3.6a was determined by X-ray analysis. A series offluoroethyl-1,2,3-triaozle nucleoside analogues were synthesized in5steps with the overall yield0.7%-2.3%via mesylation, alkylation, deprotection and derivatization.We performed the condition screening for the removal of trityl group, confirming thatrefluxed in the methanol with iodine as the optimal condition. The1H NMR and13CNMR spectrum of compound3.11b was analyzed.In Chapter4, a series of N-p-methoxybenzyl substituted1,2,3-triazole nucleosideanalogues and NH-triazole nucleoside analogues were designed and synthesized.4,5-dihydroxymethyl-1-p-methoxybenzyl1,2,3-triazole was synthesized by using2-butyne-1,4-diol as dipolarophile and p-methoxybenzyl azide as1,3-dipole viaHuisgen1,3-dipolar cycloaddtion.4-Hydroxyl was selectively protected by tritylgroup. The triazole group and purine was linked via mesylation and alkylation of5-hydroxyl. A series of N-p-methoxybenzyl substituted1,2,3-triazole nucleosideanalogues could be obtained after deprotection of trityl in a overall yield of3.6%-8.7%.6-Methoxy, ethoxy, methylamino, amino, cyclopropylamino sbustituted purinederivatives were obtained by nucleophilic aromatic substitution reaction with relatednucleoohile. NH-1,2,3-triaozle nucleoside analogues could be obtained after removalof p-methoxybenzyl group.More than100new compounds were prepared and65of them were targetmolecules, all compounds were characterized by1H NMR,13C NMR and HRMS. Theanti-HSV and anti-HBV activities of the target molecules are evaluated by Laboratoryof Virology and Chemotherapy of Leuven University in Belgium, and the activity areunder testing.