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.
| Marnera, Georgia; d'Alarcao, Marc (2006) Synthesis of galactosaminyl D-chiro-inositols. Carbohydr Res 341:1105-16 |
| Jaworek, C H; Iacobucci, S; Calias, P et al. (2001) Synthesis of inositol glycan cyclic phosphates. Carbohydr Res 331:375-91 |
| Iacobucci, S; Filippova, N; d'Alarcao, M (1995) Deprotection of p-methoxyphenyl pyranosides by anodic oxidation. Carbohydr Res 277:321-5 |
