Synthesis of alginate neoglycolipids / by Rongsong Xu.

Abstract

Innate immunity, one of two arms of the immune system, can provide more rapid defense mechanisms than adaptive immunity in human immune defense systems. The innate immune system recognizes invading pathogens by binding a variety of ligands to the family of Toll-like receptors (TLRs) which play important roles in linking innate and adaptive immunities in host immune defense. Direct application of natural TLR ligands in the pharmaceutical industry is evidently limited due to their complicated components and high toxicity, and hence synthetic TLR ligands have emerged as competitive therapeutic agents involved in various diseases including infection, inflammation and cancers. Alginates are unbranched and non-repeating linear polysaccharides comprising 1,4-linked β-D-mannuronic acid (M) and the C-5-epimer α-L-guluronic acid (G) with highly variable composition and sequential structure. They act as strong immune stimulants mediated by TLR2 and TLR4. β-1,4-D-mannuronic acid neoglycolipids (1 and 2), in this thesis, have been designed as potential ligands for TLR 2/4. The chemical synthesis of 1 and 2 have been described. Through diastereoselective β-glycosylation of the 4,6-0-benzylidene protected α-thiomannoside donor 9 with glycosylation acceptors 6, 12 and 18 respectively, followed by a series of deprotection and protection steps, the protocol successfully provides β-1,4-di- and tri-D-mannosides. Finally, the TEMPO/BAIB mediated oxidation and global hydrogenlization steps lead us to the target molecules 1 and 2: [formula]