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.
The findings and materials generated by the proposed studies in this Project will provide the key molecular information and the required synthetic compounds for establishing the important roles of several new specialized pro-resolving mediators in inflammation-resolution pathways. Ultimately, these studies will also help identify fundamentally new and improved therapeutic approaches for treating a variety of conditions involving inflammation and tissue injury, leading to improvements in patient care and unmet medical needs.
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