Synthesis of Glycomimetics and Related Structures

描述(申请人提供)：高氧四氢吡喃和环己烷是疾病相关机制的生化探针，和/或新治疗剂的药物先导。这些包括可以起到糖仿制作用的非天然碳水化合物的类似物，以及具有强大活性的天然产品。这项提议的广泛长期目标是为这类结构开发综合方法。我们已经证明，在温和的条件下，1-硫代-1，2-0-异亚丙基缩醛(TIA‘s)的活化会导致复杂的氧卡宾离子，这使得获得高含氧环系统的新方法成为可能。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基Lewis 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，以及被广泛接受的选择素结合模型，我们提出了这种C-二糖的结合构象。第一组合成目标是一组构象受限的C-糖苷类似物。这些结构的设计是为了研究选择素结合的最佳要求。这一信息与发现更有效的小分子选择素拮抗剂有关。 第二个靶点是肌醇的C连接类似物。这种结构是许多有趣的机械探针的前身，用于询问分枝杆菌中磷脂酰肌醇甘露聚糖(PIM)的生物合成和功能。因此，这种分子在与结核病和其他分枝杆菌感染相关的药物开发中是一个有价值的工具。 第三个目标是一种非天然的类似物，即高含氧量的天然产物烟美西林。烟青素的衍生物作为抗血管生成药物引起了人们的关注。药物优化需要新的结构。这种新的类似物被设计来回答关于药物特异性的问题。 该项目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.