Design,Synthesis,and Bio-Assay Of Th2-Bias ?-Galcer Analogues

The selective activation of T-cell immune activity is of great significance for the clinical application of galactosyl ceramides.In this paper,the effects of the modification of C4 or C6 positions of the sugar ring on the ?-GalCer were investigated by using the computer-assisted molecular docking technology,and the structure analysis of receptor TCR,along with the synthesis technology of organic chemistry.The biological activity was predicted by molecular docking method.Finally,the in vivo activity test verified our prediction.There are four chapters in this dissertation.In Chapter one: KRN7000 is a star moleculer of ?-GalCer compounds,which has multipul biological activities,for example,anti-tumor,anti-fugal,anti-tuberculosis.It can activate iNKT cells mediating celluar or humoral immunitu.This chapter reviews the research progress on the structural modification of KRN7000 since its initial synthesis in recent years(Modification of four parts: sugar ring,glycoside bond,ceramide and alkyl chain),and the binding sites of ligand in the triad of CD1d/?-GalCer/TCR were discussed in detail.At the same time,the structural characteristics of Th1/Th2 oriented analogues are compared and analyzed,which had guiding significance for our research work.In Chapter two: Based on the structural analysis of the receptors and the computer-assisted molecular docking calculation,we obtained a bunch of analogues by introducing carboxyl or hydrophilic aromatic groups at the end of the C6 or C4 substituent groups of OCH' s sugar group.We selected five target compounds with high TotalScore from the designed new compounds(Compound 2-5,2-9,2-10,2-11,2-12)to complete their total synthesis for the first time,and the bioactivity of 2-5,2-9,2-10 was tested.Results indicates that compound 2-5,2-9,2-10 have the potential to selectively activate the Th2 immune response,and 2-9 showed better selectivity to Th1/Th2 than OCH.In Chapter three: In this chapter,the methods of calculation,synthesis and bioassay are described in detail.