Synthesis Of PGLs Derivatives From Mycobacterium Tuberculosis

Tuberculosis caused by Mycobacterium tuberculosis is the most common global epidemic of all potentially fatal bacterial infections in the world.According to statistics,10.5 million people were infected with M.tuberculosis in 2015,leading to 1.8 million deaths worldwide.With great rise of multidrug resistant(MDR)and extensively drug resistant(XDR)strains of M.tuberculosis,480 000 new cases of MDR infections were reported in 2015.In addition,the number of tuberculosis and human immunodeficiency virus(HIV)co-infection is increasing year by year,which makes the treatment of tuberculosis more difficultThe only human vaccine that can be used to prevent tuberculosis is BCG.In recent years,many studies have shown that this vaccine has a high protection rate against children and transmitted tuberculosis.However,for adults,its protective effect on humans is very poor,and the protection rate varies greatly ranging from 0%to 80%.Therefore,it is ugrently needed to develop more effective vaccines and drugs to prevent and treat tuberculosis.The glycolipids that make up the cell wall of M.tuberculosis are considered to be important virulent factors and play key roles in host-pathogen interaction and disease pathogenesis.The trisaccharide chain of phenolipid(PGLs)consists of L-rhamnose and L-fucose and is also modified by a unique methylation pattern.Studies have shown that the PGLs trisaccharide chain is very important in the pathogenesis of M.tuberculosis and can inhibit the secretion of pro-inflammatory cytokines by host immune cells.p-Hydroxybenzoic acid derivative(p-HBADs)is also a component of bacterial cell wall.Unlike PGLs,p-HBADs has no lipid part,but the same sugar chain as PGLs.In addition,p-HBADs inhibits the pro-inflammatory response of infected macrophages.This finding demonstrtates that the sugar chain of PGLs is extremely important for the pathogenesis of bacteria,and is the most important factor in regulating biological activity.In this thesis,we have designed three trisaccharide derivatives with different methylation patterns and lipid chain lengths.Stereoselective synthesis of trisaccharide derivatives were achieved by chemical means.Thereafter,the corresponding PGLs oligosaccharide-monophosphoryl lipid A(MPLA)conjugates were efficiently prepared by click chemistry.This thesis mainly consists of the following three chapters;Chapter 1 briefly summarizes the structural characteristics and related synthetic studies of phenol glycolipids(PGLs)andp-hydroxybenzoic acid derivatives(p-HBADs)in the cell wall of M tuberculosis.Chapter 2 introduces the chemical synthesis of PGLs derivatives of M.tuberculosis.In this chapter,we used DMF solvent effect to efficiently construct the ?-glycosidic bonds,and successfully synthesized three target compounds.In synthesis of the target trisaccharide XS-?,we constructed three monosaccharide modules,including fucose module XS-4,rhamnose module XS-11,and rhamnose module XS-17,and then assembled the oligosaccharide chain from the non-reducing end to the reducing end,using N-Iodosuccinimide(NIS)and Trimethylsilyl trifluoromethanesulfonate(TMSOTf)as co-catalyst and DMF solvent effect to carry out glycosylation reaction to furnish the target trisaccharide XS-1.When synthesizing the target trisaccharide XS-?,we constructed the fucose module XS-20,rhamnose module XS-21 and rhamnose module XS-17,then assemblied the oligosaccharide chain from the reducing end to non-reducing end to obtain the target trisaccharide XS-? under the samilar glycosylation reaction conditions described above.In synthesis of the target trisaccharide XS-?,we coupled the disaccharide XS-18 and rhamnose module XS-26 under the samilar glycosylation reaction conditions to afford the trisaccharide XS-?.Chapter 3 introduces the synthesis of two monophosphoryl lipid A(MPLA)-based glycolipid complexes related to M.tuberculosis PGLs.At 0?,we selectively hydrogenolysed the azido group on propyl chain of the fully protected PGLs trisaccharide to the amino group to yield compounds XS-30 and XS-31,which were then modified with propionic acid derivatives XS-29 to produce alkynyl-modified trisaccharide derivatives.Then,alkynyl-modified trisaccharide derivatives were coupled with the monophosphoryl lipid A derivative through click chemistry reaction to furnish the target PGLs-MPLA glycolipid complexs.