SYNTHESIS OF INSULIN-MIMETIC PHOSPHOSACCHARIDES

该项目的最终目标是提供新的治疗方法 治疗非胰岛素依赖型糖尿病的药物。因为这种病 以胰岛素受体后缺陷为特征，所采用的策略 在这个提案中设计的是受体后活性分子，准备 通过化学合成并在整个细胞和细胞中对它们进行评估 胰岛素模拟活性的免费检测。化学结构 为此目的而选择的是基于最近发现的 从不同物种释放的低聚磷糖(POS) 胰岛素治疗后的胰岛素敏感细胞。这些分子是 被认为是胰岛素信号的第二信使，释放出来 通过胰岛素受体的占有率。这些POS分子都具有很强的 模拟胰岛素和受体后活性。 一系列含有甘露糖、氨基葡萄糖和肌醇的 将合成磷酸糖，每个磷酸糖构成一个定义的 天然POS的子结构。这些分子将被评估为 各种胰岛素样活动，包括对葡萄糖的调节 脂肪细胞的氧化、成脂和脂解作用及其调控 肝细胞糖原合成与糖异生。这将是 提供化学结构和生物结构之间的详细关联 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.