Synthesis And Biological Activity Study Of2’,3’-Fused Bicyclic Nucleosides

For the last decades,2’,3’-dideoxynucleosides have played considerablyimportant role for the treatment of AIDS caused by human immunodeficiency virustype1（HIV-1）. Due to the toxicity and drug resistance, medicinal chemists havepersistently explored the synthesis and activity study of these compounds for the newand better antiviral agents. It has been revealed that conformational restriction ofnucleosides by the formation of a ring system between sugar atoms would be aneffective mean to achieve the novel nucleoside analogues that may possess improvedantiviral activity. On the other hand, many triazole-containing compounds haveshown a variety of interesting biological activities and thus triazole is regarded as aprivileged structure in drug discovery. The triazole ring can be constructed by1,3-dipolar cycloaddition reaction between an azido and an alkynyl functionalities inan efficient and divergent manner. Therefore, this thesis aims at designing andsynthesizing2’,3’–triazolo fused bicyclic nucleosides via intramolecular1,3-dipolarcycloaddition reaction by alkynyl and azido groups. Furthermore, we will check theanti-HIV activity of the conformationally-constrained nucleosides in search of thebetter antiviral drug.The second chapter deals with the design and synthesis of2’,3’-bicyclicnucleosides containing triazole unit.The synthesis of2’-triazole-2’,3’-cis-bicyclic uridine started from5’-O-trity-2,2’-O-uridine by nucleophilic ring opening with NaN3to give2’-azideuridine1-4, which was then reacted with3-propargyl bromide for the introduction ofpropargyl group at3’-hydroxy of the compound. Instead of the formation ofcycloaddition prodursor1-5, we surprisely isolated the final bicyclic uridine1-6,resulted from simutanously intramolecular cyclization of cis azido and alkynylgroups under the alkynylation condition.5’-trityl was removed by a treatment of acidand we obtained5’-hydroxyl free compounds. Then the nucleobase uracil wasconverted into cytosine to give corresponding2’-triazolo-2’,3’-cis-fused bicycliccytidine1-8and1-9. The synthesis of2’-triazole-2’,3’-trans-bicyclic uridine relys on the formation of2’-azide-3’-β-hydroxy uridine2-4. We attempted to invert the configuration of3’-α-hydroxy in uridine1-4into3’-β-hydroxy uridine2-4in the following three methods:1) by Mitsunobu reaction of2’-azide-3’-α-hydroxy uridine1-4that induces anintramolecular nucleophilic substitution reaction to form2,3’-O-uridine, followed byring opening under alkaline condition;2） by mesylation of3’-α-hydroxy of2’-azide-3’-α-hydroxy uridine1-4, followed by SN2nucleophilic substitution withPhCOOK and then hydrolysis of the formed ester under alkaline condition;3)neighboring group participation between5’-benzoate and3’-O-methyl sulfonyl in2’-azide uridine and followed by hydrolysis. However, all those three attemptedmethods failed to achieve the invertion of3’-hydroxy configuration. At last, wesuccessfully synthesized2’-azide-3’-β-hydroxy uridine2-4and3’-azide-2’-β-hydroxyuridine3-4via ring opening of2’,3’-epoxy uridine2-3with sodium azide. Compound2-4was treated with NaH and reacted with3-Propargyl bromide under ultrasoniccondition to give the procusor2-5, which underwent cycloadditon at reflux in tolueneto give5’-trityl-2’,3’-trans-bicyclic uridine2-6. Similarly by the transformation asdescribed above, we synthesized2’,3’-trans-bicyclic uridine2-7and the corresponding2’,3’-trans-bicyclic cytidines2-8and2-9.The synthesis of3’-triazole-2’,3’-cis-bicyclic uridine started from mesylation of2’-β-hydroxy of3’-azide-2’-β-hydroxy uridine3-4, followed by SN2nucleophilicsubstitution with PhCOOK and then by hydrolysis of the formed ester under alkalinecondition to give3’-azide-2’-α-hydroxy uridine3-6. When compound3-6wastreated with3-propargyl bromide, intramolecular cyclization took placesimutaneously to afford bicyclic uridine3-7. Treated with acid for removal of5’-tritylprotecting group, we obtained the5’-hydroxy compound3-9. The uridine3-7wastransformed to the corresponding cytidines3-10and3-11in the same way asdescribed above.The synthesis of3’-triazolo-2’,3’-trans-bicyclic uridine4-6was achieved bypropargylation of compound3-4with3-Propargyl bromide in the presence of NaH under ultrasonic condition to compound4-5, which was then heated under reflux intoluene. Removal of trityl group under acidic condition gave5’-hydroxy compound4-7. The uridine4-7was transformed to the corresponding cytidines4-8and4-9in thesame way as described above.The third part of this thesis investigates the anti-HIV activity of the designed andsynthesized compounds. Compound4-7showed the best biological activity resultsregarding to the viral suppression and cell survival among all the tested compounds.However, no compound is superior to the reference drug AZT in activity and toxicityin the tested assays.