Design Synthesis And Biological Activity Study Of Polyvalent Double-fluoro-substituted Sialic Acid Conjugates

Flu,witch with the characteristics of infectious strongly and the high incidence of susceptibility crowd,is a kind of acute viral respiratory infection caused by influenza viruses treats to human health seriously.One of the reasons of its high prevalence rate is the high variability of its antigen.Amantadine/rimantadine and viral vaccines are mainly responsible for the treatment of flu until the development of inhibitors of neuraminidase.In 1980s,Colman,et al.,discovered that the NA identified and fractured neuraminidase at the unique site and played an important role in the process of virus’s release.The inhibition of NA can restrain the replication of virus DNA and flu is cured consequently.Thus,the research and development of NA’s inhibitors on the basis of sialic acid have become a hot spot in the field of the development of anti-flu drugs.To date,two analogs of sialic acid-Zanamivir and Oseltamivir have been listed.Zanamivir using fluorine atoms to form a double-fluoro-substituted compound,in which the upright bond conformation of 3-fluoro performed stronger inhibition to NA than the equatorial one.After introduction of fluoro,Zanamivir showed better inhibition activity for resistant strains but less effect on normal strains than Zanamivir and Oseltamivir.Through extensive literature investigation,we plan to design a serial of multivalent Zanamivir compound mediated by N3 linker and framework decorated by Carbon carbon triple bond at the C-7 of Zanamivir.Some steps as follows are taken toward this end.First,sialic acid as raw materials,carboxy methyl ester,full acetylation,the 2,3-double bond and the introduction of four protective-NHBoc,then after 8,9 bit selective protection,the introduction of seven Linker,2,3 4 guanidine performed after the introduction of the F group,to give the desired monomer,last monomer with a polyvalent skeleton Click reaction of a polyvalent substituted Zanamivir double F conjugate.Nine kinds of multivalent conjugates are sythsized in this work,and among of them show better inhibitory activity to H7N9(VLP)than monomer.Especially,the one conjugated from polyethylene maleic anhydride reach the best efficient IC50 less than 0.54nM.