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

特异性促消退介体（SPM）包括消退素、保护素和最近发现的maresins，它们的一个重要特征是它们都具有精细的结构/功能特征，即它们的强效、受体特异性和特异性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，这些新介质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纯材料，这只能通过专业的全有机合成获得。在我们之前的努力中，我们已经开发了用于制备一系列衍生自多不饱和脂肪酸的SPM的化学方法和策略。这些SPM的特征在于关键的立体化学特征，包括Z/E双键几何结构和R/S立体化学，这需要专门的合成方法。制备这些通常不稳定的分子的立体化学纯的形式是必不可少的深入研究他们的生物概况。 本项目将研究和验证以下假设：最有效的，内源性产生的，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，消退素、保护素和maresins的有效生物促消退作用在本质上是立体特异性的，并且与这些分子的某些立体化学特征相关。该项目的具体目标是： (1)建立新SPM的完整结构和立体化学。立体控制合成选定的异构体纯异构体的新resolvins，maresins，和其他新发现的SPM将被追求，它们的结构和性能将与那些生物源化合物进行比较。 (2)阐明新SPM的生物合成途径。详细的生物合成途径maresins，resolvins和相关的SPM，将采用立体控制策略的合成可能的生物合成的环氧化物中间体，这将被用作生物合成的前体。 (3)研究新SPM的立体专一性生物学作用。通过与其他项目和核心的合作，将建立这些SPM的有效促分解特性所需的结构特征，从而为治疗涉及炎症和组织损伤的疾病提供新的方法。

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.