Biological Targets from Oxetane Templates

描述(申请人提供)：应变杂环存在于许多重要的生物分子中，由于它们的反应性和传递手性信息的能力，它们作为合成中间体发挥着关键作用。我们建议使用我们开发的以氧杂乙烷为中心的方法来制备分子，这些分子解决糖脂在免疫调节中的作用，以及可能在病毒、细菌和自身免疫性疾病、癌症治疗和控制蚊子种群中具有治疗应用的化合物。最近的研究发现，CD1蛋白家族是一种新的抗原提呈分子，由位于MHC外的基因编码。此外，CD1呈递的抗原主要是糖脂。结构、生化和生物物理研究表明，CD1蛋白与抗原的疏水烷基部分结合，并定位结合脂类的极性头基，以便与T细胞受体发生特定的相互作用。虽然对CD1家族的研究还处于初级阶段，但该家族已经与青少年糖尿病、多发性硬化症、疟疾和癌症等世界性疾病有牵连。该家族的成员之一CD1d被发现是KRN7000的抗原提呈蛋白，KRN7000是一种α-半乳糖基神经酰胺，目前正处于临床试验中，用于治疗转移性癌症。与CD1家族相关的巨大治疗潜力意味着，了解影响糖脂与CD1抗原递呈蛋白相互作用的因素以及它们随后与特定T细胞受体的结合是及时而重要的。这项建议的重点是利用我们开发的方法学来制备一套设计合理的糖基神经酰胺，这些神经酰胺在神经酰胺和糖表位上都不同，以探索脂类和糖在免疫反应中的作用。用于构建糖脂的神经酰胺部分的支架是丝氨酸衍生的氧杂环己酮。这种多用途的模板可以有效地转化为氨基二醇、氨基三醇或4，5-不饱和氨基二醇狮身人面像碱，这些碱很容易转化为神经酰胺。制备的鞘糖脂将被用来检测生物物理参数，如解离常数和t1/2s与免疫反应的性质之间的关系。此外，还将检测IL-2、IL-4和干扰素-γ的释放水平，以了解结构对细胞因子释放的影响。那些释放高水平IL-4的化合物将被研究其治疗自身免疫性疾病的潜力。此外，月桂酸苷是一种对淡色库蚊蚊子幼虫具有良好活性的化合物，将从1，5-二氧杂螺[3.2]己烷模板中合成，并被评估为抗疟疾蚊媒的杀幼虫药物。与疟疾相关的大规模全球发病率和死亡率、当前类别中杀虫剂抗药性的上升以及新类别的缺乏使这一项目变得及时。

DESCRIPTION (provided by applicant): Strained heterocycles are found in a number of biologically important molecules and play a key role as synthetic intermediates because of their reactivity and their ability to relay chiral information. We propose to employ methodology we have developed centered around oxetanes to prepare molecules that address the role of glycolipids in immunomodulation and compounds that may have therapeutic applications in viral, bacterial, and autoimmune diseases, in cancer treatment and in control of mosquito populations. Recent studies have identified the CD1 family of proteins as novel, antigen-presenting molecules encoded by genes located outside of the MHC. Further, the antigens presented by CD1 are largely glycolipids. Structural, biochemical and biophysical studies suggest that the CD1 proteins bind the hydrophobic alkyl portions of the antigens and position the polar head groups of the bound lipids for specific interactions with the T cell receptors. Although the investigations of the CD1 family are in their infancy, already this family has been implicated in such worldwide diseases as juvenile diabetes, multiple sclerosis, malaria and cancer. One member of the family, CD1d, has been found to be the antigen presenting protein for KRN7000, an alpha-galactosyl ceramide currently in clinical trials for the treatment of metastatic cancer. The tremendous therapeutic potential associated with the CD1 family means that an understanding of the factors influencing interactions of the glycolipids with CD1 antigen-presenting proteins and their subsequent engagement of specific T cell receptors is timely and important. The focus of this proposal is the exploitation of methodology we have developed to prepare a rationally designed set of glycosyl ceramides that vary in both the ceramide and sugar epitopes in order to probe the role of both the lipid and the saccharide in immunological responses. The scaffold for the construction of the ceramide portion of the glycolipids is a serine-derived oxetan-2-one. This versatile template can be efficiently transformed to aminodiols, aminotriols or 4,5-unsaturated aminodiol sphingoid bases that are readily converted to ceramides. The glycosphingolipids prepared will be used to examine the relationship between biophysical parameters such as dissociation constants and t1/2s and the nature of the immune response. Moreover, the level of release of IL-2, IL-4 and IFN-gamma will be assayed in order to gain an understanding of structural effects on cytokine release. Those compounds that release high levels of IL-4 will be investigated for their therapeutic potential for the treatment of autoimmune conditions. In addition, laureatin, a compound that has shown promising activity against Culex pipiens pallens mosquito larvae, will be synthesized from a 1,5-dioxaspiro[3.2]hexane template and be assessed as a larvicide against malarial mosquito vectors. The massive worldwide morbidity and mortality associated with malaria, the rise of insecticide resistance in the current classes, and the dearth of new classes make this a timely project.