SYNTHESIS OF INSULIN-MIMETIC PHOSPHOSACCHARIDES

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This project is aimed at the ultimate goal of providing novel therapeutic agents for non-insulin dependent diabetes mellitus. Since this disease is characterized by a post insulin-receptor defect, the strategy employed in this proposal is to design post-receptor active molecules, prepare them by chemical synthesis and evaluate them in both whole cell and cell free assays for insulin-mimetic activity. The chemical structures selected for this purpose are based on recently discovered phosphooligosaccharides (POS) which are released from various insulin-sensitive cells upon insulin treatment. These molecules are believed to be soluble second messengers of the insulin signal, released by insulin-receptor occupancy. These POS molecules are both potently insulin-mimetic and post-receptor active. A series of mannose, glucosamine, and myo-inositol-containing phosphosaccharides will be synthesized, each constituting a defined substructure of the natural POS. These molecules will be evaluated for various insulin-like activities including modulation of glucose oxidation, lipogenesis, and lipolysis in adipocytes, and modulation of glycogen synthesis and gluconeogenesis in hepatocytes. This will provide a detailed correlation between chemical structure and biological activity for this class of compounds.