SYNTHESIS AND SPECTROSCOPY OF PHOSLIPID ANALOGUES

新的合成方法的发展为制备 结构上定义明确的磷脂化合物已经成为一种及时的 而且是一个重要的问题，因为人们发现除了他们的 磷脂是所有生物膜中的主要成分 还参与了广泛的生理和调节过程。 磷脂对许多细胞的功能是必不可少的 膜结合酶，如蛋白激酶C，并发挥作用 在信号转导中作为生产底物的重要作用 第二信使(肌醇-1，4，5-三磷酸肌醇、二酰甘油)和在 花生四烯酸的释放。值得注意的是，一些最强大的 磷脂化合物，其活性低于微摩尔和 纳摩尔水平在细胞中以低浓度出现，因此 合成衍生品的制备是一个明确的先决条件 阐明它们的生化作用机制。主要目标 提议的项目的目的是开发新的合成方法 磷脂衍生物的制备，包括含 光谱活性报道基团及其表征 膜模型中的结构探针(胶束和囊泡)。这个 方法将侧重于发展五国的化学 1，3，2-二氧磷环及其取代衍生物的阐述 磷酸二酯靶和结构上相关的类似物。合成材料 应用将集中在1)二酰基甘油磷脂的制备 具有顺磁和荧光能量的光谱探针 转移供体-受体报告基团，2)过渡态类似物 磷脂酶A2酶的抑制剂，以及3)含 一个BH3基团取代了其中一个非桥联磷酸氧基 磷酸二酯功能。一种新的电子自旋共振研究 制定的“指标加宽法”将在 首席合作调查员确定结构组织和 单标和双标脂肪酰基侧链的动力学 磷脂。已作出合作安排，以评估 作为磷脂酶A2底物和抑制剂的合成化合物。 此外，它们的热致行为和促进VS的作用。 抑制小泡之间的胆固醇交换也将被确定。

Development of new synthetic methods for the preparation of structurally well-defined phospholipid compounds has become a timely and important problem since it was discovered that in addition to their role as a major component in all biological membranes phospholipids are also involved in a wide range of physiological and regulatory processes. Phospholipids are essential for the functioning of a number of membrane-bound enzymes such as protein kinase C, and play an important role in signal transduction as substrates for the production of second messengers (inositol-1,4,5-trisphophate, diacylglycerol) and in the release of arachidonic acid. Significantly, some of the most potent phospholipid compounds, which are active below the micromolar and nanomolar levels occur in low concentrations in the cell, such that preparation of synthetic derivatives represents a clear prerequisite to elucidation of their biochemical mechanism of action. The main objective of the proposed project is to develop new synthetic methods for the preparation of phospholipid derivatives, including compounds with spectroscopically active reporter groups and their characterization as structural probes in membrane models (micelles and vesicles). The approach will focus on developing the chemistry of the five-membered 1,3,2-dioxaphospholane ring and its substituted derivatives to elaborate phosphodiestertargets and structurally related analogues. The synthetic application will focus on preparation of 1) diacylglycerophospholipid spectroscopic probes with paramagnetic and fluorescence energy transfer donor-acceptor reporter groups, 2) transition-state analogue inhibitors of phospholipase A2 enzymes, and 3) boranophopholipids with a BH3 group replacing one of the nonbriding phosphate-oxygens in the phosphodiester function. Electron spin resonance studies using a newly developed "indicator broadener method" will be conducted in the principal co-investigator's to determine the structural organization and dynamics of fatty acyl side chains of single- and double-labeled phopholipids. Collaborative arrangements have been made to evaluate the synthetic compounds as phospholipase A2 substrates and inhibitors. In addition, their thermotropic behavior and role in promoting vs. Inhibiting cholesterol exchange between vesicles will also be determined.