SYNTHESIS OF INSULIN-MIMETIC PHOSPHOSACCHARIDES

该项目旨在提供新的治疗方法， 用于非胰岛素依赖型糖尿病的药物。 由于这种疾病 其特点是胰岛素受体后缺陷， 在本方案中是设计受体后活性分子，制备 它们通过化学合成，并在整个细胞和细胞中评估它们 模拟胰岛素活性的免费检测。 的化学结构 为此目的选择的是基于最近发现的 磷酸寡糖（POS），从各种 胰岛素敏感性细胞在胰岛素治疗后。 这些分子 被认为是胰岛素信号的可溶性第二信使， 通过胰岛素受体占有率。 这些POS分子都能有效地 胰岛素模拟物和后受体活性。 一系列含有甘露糖、葡萄糖胺和肌醇的 将合成磷酸盐，每一个构成一个定义的 自然POS的子结构。 这些分子将被评估为 各种胰岛素样活性，包括葡萄糖的调节 脂肪细胞中的氧化、脂肪生成和脂解，以及 肝细胞中糖原合成和糖原生成。 这将 提供了化学结构和生物学之间的详细关系， 这类化合物的活性。

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.