Synthesis And Characterization Of Novel N-arylaminotriazole Nucleosides And Their Biological Evaluation

Nucleoside mimics, created by modification either on nucleobase and/or on theribose of the natural nucleosides, are a class of important candidates to search forantiviral and anticancer drugs. One of the best representatives is ribavirin, which bearsan unnatural but unique1,2,4-triazole heterocycle. Ribavirin is the first synthetictriazole nucleoside, which displays an extremely large spectrum of antiviral activity.Over a long period, ribavirin remained as the only clinically available small moleculeto treat the infection caused by hepatitis C.We are interested in developing novel triazole nucleosides in the quest tosearching for antiviral and anticancer drug candidates. As we know, triazole is anunnatural base, the resulting triazole nucleosides may hence be resistant tonucleos(t)ide metabolizing enzymes and endowed with increased in vivo stability andefficiency. In addition, triazole heterocycle is a universal base for base-pairing, whichmay offer beneficial interaction with nucleic acids. Finally, expanding the triazolenucleobase by appending aromatic systems may favor stronger and more efficientbinding to biological targets. Based on these considerations, we have been activelyengaged in exploring various synthetic strategies during the last ten years to constructa molecular library consisting of structurally novel and diverse triazole nucleosidesmainly in the way of introducing π-conjugated systems onto the triazole nucleobase.In this thesis, we are particularly concerned in developing highly efficientmethods to synthesize the N-arylaminotriazole nucleosides (Figure1). This is becauseour previous results showed that some of these nucleoside analogs (2-1,4-1)possessed of potent anticancer activity involving novel mechanisms of action.Figure1The desired productsHowever, our previous synthesis based on Cu-mediated Chan-Lam reaction wasonly able to yield the N-aryl aminotriazole nucleosides (2-1,4-1), which was far fromsatisfaction as the synthesis suffered from long reaction time, large catalyst loading,low yields and narrow substrate scope of both aryl bronic acid and triazole nucleoside.We therefore explored several approaches for synthesizing this family of compounds during my PhD program.We first attempted microwave irradiation to promote Chan-Lam C-N coupling.Whereas the reaction time was significantly reduced, no beneficial effect wasachieved with regards to improve the reaction yield, decrease the catalyst loading andenlarge the substrate scope etc (Figure2).Figure2Microwave-assisted Chan-Lam reactionWe then turned our attention to Pd-catalyzed Buchwald-Hartwig amination anddiscovered highly reactive Pd/ligand systems employing the phosphor ligands,Synphos and Xantphos, for selective aryl amination with the5-and3-bromotriazoleacyclonucleoside isomers, respectively, affording the correspondingN-arylaminotriazole acyclonucleosides with good to excellent yields (Figure3). Theligand mediated C-N coupling provided us an exceptionally extended scope of arylamine but could not extend scope of triazole nucleoside, with the synthesis beinghandicapped with limited nucleoside starting materials.Figure3Selective Buchwald-Hartwig AminationWe therefore developed a mixed-ligand system of Pd/Synphos/Xantphos, whichpromotes effectively C-N coupling in the synthesis of various N-arylaminotriazoleand N-arylaminopurine nucleoside analogues. This catalytic system is strikinglypowerful and efficient, allowing for unparalleled substrate scope and high productyields as well as promotion of C-Cl bond activation for C-N coupling. Further31PNMR studies led us to propose a general mechanism involving two independentcatalytic cycles between which Pd is shuttled (Figure5). Further development of mixed-ligand catalysts to promote synthesis of other types of triazole nucleosideanalogues is currently under the way in our group.Figure4Mixed-ligand promoted aryl aminationFigure5Proposed mechanism of the mixed-ligand systemFinally, we assessed all of the newly synthesized N-aryl aminotriazolenucleosides for antiviral and anticancer test. Pleasingly, some of them displayedoutstanding anticancer activity against drug-resistant pancreatic cancer, with superiorpotency compared to gemcitabine, the current first-line drug to treat pancreatic cancer.This finding further confirmed and warranted the interest in and importance ofdeveloping efficient catalytic systems for synthesizing this special family ofnucleoside analogs. We are actively pursuing our efforts and endeavor in thisdirection.