Synthesis And Biological Evaluation Of Glycolipids Simplexides And Glycosphingolipid Derivatives

Glycolipids are membrane components composed of lipids that are covalently bonded to monosaccharides or polysaccharides. The occurrence of glycolipids which contain glycosphingolipids, glycoglycerolipids, polyprenol phosphate glycoside and sterol glycosides have an important regulatory role in the cell growth, differentiation and apoptosis, and some of them are potential therapeutic drugs. Recently, glycolipids have been proved to involve in immune response. Immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to prevent the rejection of transplanted organs and tissues. But these drugs are not without side-effects and risks. Because the majority of them act non-selectively, the immune system is less able to resist infections and the spread of malignant cells. In this dissertation, the first synthesis of novel glycolipids simplexides (1a-c) has been achieved through a straightforward and several analogues of glycosphingolipids were designed and synthesized for the future evaluation in immunoregulatory activity.(1) The first synthesis of three natural glycolipids simplexides (1a-c), which were isolated from the marine sponge Plakortis simplex and claimed to inhibit T cell proliferation, has been concisely accomplished by a reactivity-based one-pot synthetic strategy. The donor of p-methylphenyl 2, 3, 4 tri-O-benzyl-6-O-tert-butyldiphenylsilyl -1-thio-β-D-glucopyranoside can give highα-selectivity of the glycosylation. By performing the first glycosylation in Et2O/CH2Cl2 (V:V, 4:1) and the second in Et2O/CH2Cl2 (V:V, 2:3), one-pot glycosylation took place successfully in good yields.(2) For further study on the mechanism of the bioactivity, we synthesized a series of glycosphingolipids derivatives. An efficient and practical route to synthesis dihydro-glycosylsphingolipids was developed. The mesylate 34 was converted into dihydrosphingosine 36, by a series of functional group thansformation involving: reduction of the double bond and deprotection of the benzyl groups to the corresponding 35, SN2 replacement of the mesylate group in compound 35 by sodium azide to afford 36. With different glycosyl donors, 36 can be glycosylated directly to achieve dihydro-glycosylsphingolipids.This paper provides a facile and efficient approach to synthesiz galactosylceramide with a modified 2-position under the use of 3, 4, 6-tri-O-acetyl-2-O-Lev-α-D-galactopyranosyl trichloroacetimidate.(3) The minimal fungicidal concentration of T1-T20 was determined for Candida albicans, Candida parapsilosis and Candida tropicalis. We tested the possibility that the antifungal activity was manifested through nonspecific amphiphilic properties of long-chain aminolipids. The structure-activity relationship has been described as follows:①The amino-group may play an important role in the activity;②The glycosyl residue is not only a group as pharmacokinetics but also as pharmacodynamics, and has an important relationship with specificity of antifungal activity;③The long alkyl chains are necessary for antifungal activity.