Synthesis,Characterization And Biological Activity Of Novel Triazole Nucleoside Analogues

Currently,many drugs of anti-human immune deficiency virus?HIV??hepatitis B virus?HBV??hepatitis C virus?HCV?infection are nucleoside compounds in clinical.Nucleosides involve in the processes including preservation ? replication and transcription of genetic information in organisms.Nucleoside analogues are so similar to natural nuleoside structures that virus can't recognize them easily.Many nucleoside analogues inhibit or block the replication of the virus by inhibiting the activity of viral DNA polymerase and reverse transcriptase,meanwhile,they compete with natural nucleosides in a viral DNA strand.However,the use of nucleoside drugs has been relatively limited by their toxicity and drug resistance.Thus,the structural optimization of nucleoside compounds is particularly important.Nucleoside compounds are obtained by modifying the sugar ring or base or both at the same time based on the natural nucleoside structures.Sofosbuvir as nucleoside compound was approved by the FDA in 2013 for the treatment of four genotypes of HCV.According to the structure of Sofosbuvir,the most prominent feature is the presence of 2'-?-methyl-2'-?-fluoro.Ribavirin is a nucleoside drug used to inhibit HCV replication,its novelty lies in the triazole base.Triazole has been introduced into the structural modification of nucleosides by many researchers because of its non-toxic,water-soluble,stable,broad-spectrum bioactivity and other advantages.Our laboratory has long been committed to the synthesis of nucleoside compounds.Based on the structure of 2'-?-methyl-2'-?-fluoro skeleton,we have synthesized a series of nucleoside comounds in which 1,2,3-triazole as base group,meanwhile,by introducing azide group and fluoro group at the 4'-position of the sugar group,we synthesized two new kinds of nucleoside compounds 20 and 24.Antiviral activity tests were performed on these nucleoside analogues which are expected to obtain better antiviral activity.?1?5-7?Two configurations of ? and ???11?12 eight kinds of 1,2,3-triazole nucleoside analogues were synthesized through SN2,click and deprotection reactions from 2'-?-methyl-2'-?-fluoro-modified saccharide lactone which serves as starting material.We further synthesized the 7-? monophosphate compound 14.The structures of these compounds were confirmed by ¹H NMR,¹³ C NMR and HRMS.Furthermore,the compounds of 5-? and 7-? were confirmed by X-ray diffraction apparatus.?2?The results showed that these compounds did not show obviously excellent activity of inhibiting the replication of HIV and HCV.?3?4'-azide group and 4'-fluoro group are introduced into 7-? compound respectively by elimination,addition,protection,oxidation,deprotection reactions.Finally,we obtained 4'-azide-1,2,3-trizole nucleoside compound 20 and 4'-fluoro-1,2,3-trizole nucleoside compound 24 which are expected to achieve better antiviral activity.