The goal is to gain an understanding at the molecular level of the mechanism of action of the antifungal properties associated with the polyene macrolide antibiotics. The design and synthesis of unnatural compounds will be pursued with the objective of realizing antifungal agents of improved therapeutic efficacy. This study is simultaneously pursuing three interrelated avenues of investigation: a. the development of a general synthetic approach the polyene macrolide class of antibiotics, b. the synthesis of simplified polyene macrolide analogs, and c. physical studies aimed at understanding the structural details of the critical polyene-sterol interactions required for fungicidal activity. Within the context of the synthetic studies, general problems in acyclic asymmetric synthesis are being addressed, principally through diastereoselective elaboration of L-aspartic acid. As synthetic methodology is developed, access to increasingly diverse analogs to the natural polyene macrolides becomes available to test the structural features of these compounds that lead to selective binding with certain sterols. These studies are further supported by spectroscopic (i.e., NMR) efforts to directly observe the polyene-sterol pairs in solution, micelles, and in membranes.
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