Synthesis of Glycomimetics and Related Structures

描述（由申请人提供）：高度氧化的四氢吡喃和环己烷作为疾病相关机制的生物化学探针和/或新治疗剂的药物先导物是令人感兴趣的。这些包括可以作为糖模拟物的碳水化合物的非天然类似物，以及具有有效活性的天然产物。该提案的广泛的长期目标是开发此类结构的合成方法。我们已经表明，1-硫代-1，2-0-异亚丙基缩醛（TIA）在温和条件下的活化，导致复杂的氧代碳正离子，这使得新的方法高度氧化的环系统。在这个项目中，TIA化学将应用于三个特定领域的合成。 我们制备了一种新的唾液酸刘易斯X的C-二糖模拟物，并测定了它的形成行为和与P-选择素的结合。基于这些信息，sLex的溶液构象，和广泛接受的选择素结合模型，我们提出了一个结合的构象为这个C-二糖。第一组合成靶标是该C-糖苷的一组构象受限制的类似物。这些结构已被设计为研究选择素结合的最佳要求。该信息与发现更有效的小分子选择素拮抗剂有关。 第二个靶标是肌醇的C-连接类似物。这种结构是一个通用的前体，许多有趣的机械探针，用于询问的生物合成和功能的磷脂酰肌醇甘露聚糖（PIM）在分枝杆菌。因此，这种分子构成了与结核病和其他分枝杆菌感染相关的药物开发的有价值的工具。 第三个目标是高度氧化的天然产物烟曲霉素的非天然类似物。烟曲霉素的衍生物作为抗血管生成剂已引起关注。药物优化需要新的结构。这种新的类似物被设计来回答药物特异性的问题。 该项目中开发的方法有望对碳水化合物识别和合成的其他领域具有更广泛的意义。

DESCRIPTION (provided by applicant): Highly oxygenated tetrahydropyrans and cyclohexanes are of interest as biochemical probes for disease related mechanisms, and, or drug leads for new therapeutic agents. These include unnatural analogs of carbohydrates that can act as glycomimetics, and natural products with potent activity. The broad long-term goal of this proposal is the development of synthetic methodology for such structures. We have shown that activation of 1-thio-1,2-0- isopropylideneacetals (TIA's) under mild conditions, lead to complex oxocarbenium ions, and this allows for novel approaches to highly oxygenated ring systems. In this project TIA chemistry will be applied to synthesis in three specific areas. We have prepared a novel C-disaccharide mimetic of sialyl Lewis X and determined its formational behavior and binding to P-selectin. Based on this information, the solution conformations of sLex, and the widely accepted model for selectin binding, we have proposed a bound conformation for this C-disaccharide. The first group of synthetic targets are a set of conformationally restrained analogs of this C-glycoside. These structures have been designed to investigate the optimal requirements for selectin binding. This information is relevant to the discovery of more potent, small molecule, selectin antagonists. The second target is a C-linked analog of myoinositol. This structure is a versatile precursor to a number of interesting mechanistic probes for interrogating the biosynthesis and function of phosphatidylinositol mannans (PIM's) in mycobacteria. This molecule therefore constitutes a valuable tool in drug development related to tuberculosis and other mycobacterial infections. the third target is an unnatural analog of the highly oxygenated natural product fumagillin. Derivatives of fumagillin have attracted attention as anti-angiogenic agents. Novel structures are in demand for drug optimization. This new analog has been designed to answer questions on drug specificity. The methods developed in this project promise to be of wider significance to other areas of carbohydrate recognition and synthesis.