Strained heterocycles are found in a number of biologically important molecules and play a key role as synthetic intermediates because of their reactivity and their ability to relay chiral information. We propose to employ methodology we have developed centered around oxetanes to prepare molecules that address the role of glycolipids in immunomodulation and compounds that may have therapeutic applications in viral, bacterial, and autoimmune diseases, in cancer treatment and in control of mosquito populations. Recent studies have identified the CD1 family of proteins as novel, antigen-presenting molecules encoded by genes located outside of the MHC. Further, the antigens presented by CD1 are largely glycolipids. Structural, biochemical and biophysical studies suggest that the CD1 proteins bind the hydrophobic alkyl portions of the antigens and position the polar head groups of the bound lipids for specific interactions with the T cell receptors. Although the investigations of the CD1 family are in their infancy, already this family has been implicated in such worldwide diseases as juvenile diabetes, multiple sclerosis, malaria and cancer. One member of the family, CD1d, has been found to be the antigen presenting protein for KRN7000, an alpha-galactosyl ceramide currently in clinical trials for the treatment of metastatic cancer. The tremendous therapeutic potential associated with the CD1 family means that an understanding of the factors influencing interactions of the glycolipids with CD1 antigen-presenting proteins and their subsequent engagement of specific T cell receptors is timely and important. The focus of this proposal is the exploitation of methodology we have developed to prepare a rationally designed set of glycosyl ceramides that vary in both the ceramide and sugar epitopes in order to probe the role of both the lipid and the saccharide in immunological responses. The scaffold for the construction of the ceramide portion of the glycolipids is a serine-derived oxetan-2-one. This versatile template can be efficiently transformed to aminodiols, aminotriols or 4,5-unsaturated aminodiol sphingoid bases that are readily converted to ceramides. The glycosphingolipids prepared will be used to examine the relationship between biophysical parameters such as dissociation constants and t1/2s and the nature of the immune response. Moreover, the level of release of IL-2, IL-4 and IFN-gamma will be assayed in order to gain an understanding of structural effects on cytokine release. Those compounds that release high levels of IL-4 will be investigated for their therapeutic potential for the treatment of autoimmune conditions. In addition, laureatin, a compound that has shown promising activity against Culex pipiens pallens mosquito larvae, will be synthesized from a 1,5-dioxaspiro[3.2]hexane template and be assessed as a larvicide against malarial mosquito vectors. The massive worldwide morbidity and mortality associated with malaria, the rise of insecticide resistance in the current classes, and the dearth of new classes make this a timely project. ? ?
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