International Research Fellowship Program: Synthesis and Activity of Amphotericin B Derivatives

Wurtz Nicholas R, Pasadena CA

Investigators

Abstract

0202410 Wurtz The International Research Fellowship Program enables U.S. scientists and engineers to conduct three to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad. This award will support a twenty-four month research fellowship by Dr. Nicholas R. Wurtz to work with Dr. Erick M. Carreira at Eidgenossische Technische Hochschule (ETH) in Zurich, Switzerland. This project will be co-supported by the Math and Physical Sciences Directorate's Office of Multidisciplinary Activities. A study of the molecule, Amphotericin B (AmB), will be carried out with Dr. Erick M. Carreira. AmB remains one of the most important and effective antifungal drugs with a broad range of activity. While it is generally accepted that the mode of action of AmB is the creation of lethal pores in fungal cell membranes, little is known about the exact mechanism of pore formation or what structural aspect allows for selectivity of fungal over mammalian cells. Synthesis of AmB derivatives for mechanistic studies has been limited since published routes do not allow synthesis of sufficient quantities for assays. An improved efficient modular synthesis of AmB and subsequent analogues is proposed. The synthesis will combine the best aspects of published syntheses with methodology recently developed in Dr. Carreira's group. The analogues will be assayed for their propensity to form pores using liposomes designed to mimic mammalian and fungal cell membranes. The proposed synthesis and characterization of AmB analogues will provide insight about pore architecture and potentially the discovery of structural features that allow the design of less toxic derivatives that retain potent the antifungal activity of AmB. Dr. Carreira's program at ETH is at the forefront of asymmetric synthesis of biologically active, stereochemically complex, natural products.