The objective of this supplement proposal is to develop further the synthetic organic chemistry necessary to prepare additional quantities of a powerful immunostimulant, the C-glycoside analog of KRN7000. Key chemistry uses either the Ramberg-Backlund reaction or nitrile oxide cycloaddition methodology. In addition, an aim of this proposal is to synthesize modified fatty amide derivatives of our immunostimulant material in order to improve its solubility in common solvents without compromising its bioactivity. A further, important objective is to validate the mechanism of action of our material by comparing bioactivity in mice with and without the ability to produce NKT cells. We will continue to test our synthetic materials in a malaria assay in mice. There are two prime reasons for developing our material as a powerful inducer of NKT cells, the apparent mechanism of action as an analog of KRN7000. One fact is that diseases other than malaria (e.g. cancer and juvenile onset diabetes) are also susceptible to KRN7000 and there is reason to believe that our synthetic material behaves in the same way. The second fact is that our analog, different from KRN7000, is not susceptible to hydrolysis by endogenous mammalian enzymes.
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