Project 4:Total Synthesis of Novel Specialized Pro-Resolving Lipid Mediators

专门化的前拆分介体(SPM)的一个重要特征是所有这些分子都呈现出精致的结构/功能，即它们的强效、受体特异性和专一性的生物学作用与其分子结构的立体化学和取代模式之间的密切关系。 因此，这些新介体的完整结构表征和生物学研究需要生产已知立体化学的异构性纯材料，而这些材料只能通过专家的全有机合成获得。在我们之前的工作中，我们已经开发了从多不饱和脂肪酸中提取的一系列SPM的化学方法和策略。这些SPM具有关键的立体化学特征，包括Z/E双键几何和R/S立体化学，这需要专门的合成方法。以立体化学纯形式制备这些通常不稳定的分子对于深入研究它们的生物学特性是必不可少的。 本项目将调查和验证以下假设：最有效的、内源产生的和生物相关的SPM是通过涉及关键环氧化物中间体的专门生物合成途径以立体控制的方式产生的。此外，有效的生物亲和拆分作用的分离素，保护素和松脂，在性质上是立体专一性的，并与这些分子的某些立体化学特征有关。该项目的具体目标是： (1)建立新的SPM的完整结构和立体化学。将继续进行立体控制合成新的溶剂素、树脂和其他新发现的SPM的精选异构体，并将它们的结构和性能与生物源化合物的结构和性能进行比较。 (2)阐明新SPM的生物合成卵波。通过采用立体控制策略来合成可能的生物合成环氧化物中间体，以将其用作生物合成前体，将研究松香、分解素和相关SPM的详细生物合成途径。 (3)研究新型SPM的立体定向生物学作用。在与其他项目和核心的合作下，将确定这些SPM强大的促进分解特性所需的结构特征，从而产生治疗涉及炎症和组织损伤的疾病的新方法。

A key characteristic of the specialized pro-resolving mediators (SPM), including the resolvins, protectins and the recently identified maresins, is that all of these molecules tend to exhibit an exquisite structure/function proflle, i.e. the close relationship between their potent, receptor-specific, and specialized biological actions with the stereochemistry and substitution patterns of their molecular structures. Consequently, the complete structural characterization and biological study of these new mediators requires the production of isomerically pure materials of known stereochemistry, that can only be obtained via expert total organic synthesis. In our prior efforts we have developed chemical methodologies and strategies for the preparation of a range of SPM derived from polyunsaturated fatty acids. These SPM are characterized by key stereochemical features, including Z/E double bond geometry and R/S stereochemistry, that requires specialized synthetic approaches. The preparation ofthese often labile molecules in stereochemically pure form is essential for the in-depth investigation of their biological profiles. This Project will investigate and validate the following hypothesis: The most potent, endogenously produced, and biologically relevant SPM are produced in stereocontrolled manner by specialized biosynthetic pathways involving key epoxide intermediates. Moreover, the potent biological pro-resolving actions of the resolvins, protectins and maresins, are stereospecific in nature and are associated with certain stereochemical features ofthese molecules. The specific aims of this Project are: (1) Establish the complete structure and stereochemistry of new SPM. The stereocontrolled synthesis of selected isomerically pure isomers of new resolvins, maresins, and other newly discovered SPM will be pursued, and their structures and properties will be compared with those of biogenic compounds. (2) Elucidate the biosynthetic oathwavs of new SPM. The detailed biosynthetic pathways ofthe maresins, the resolvins and related SPM, will be investigated by employing a stereocontrolled strategy for the synthesis of likely biosynthetic epoxide intermediates, which will be utilized as biosynthetic precursors. (3) Investigate the stereospecific bioloaical actions of new SPM. In collaboration with the other Projects and Cores, the structural features required forthe potent pro-resolving properties ofthese SPM will be established, leading to new approaches for treating diseases involving inflammation and tissue injury.