This study will develop an efficient and flexible synthetic route to the polyene macrolide antibiotic class of compounds. With this in mind, the immediate goal will be the total synthesis of amphotericin B, the only compound of this class for which the stereochemistry is known. The synthetic strategy incorporates the use of readily available amino acids as chiral, versatile starting materials. In addition, this study will explore the possibilities for acyclic stereoselection mediated by intramolecular chelation. The polyene macrolide antibiotics are potent antifungal agents and are clinically important in the treatment of human mycoses. However, their toxicity presents the use of these drugs in many instances when they would be most beneficial. Therefore, a longer term goal of these studies is to develop an ergosterol-specific polyene antibiotic which holds promise of extremely low toxicity while retaining the desired antifungal properties. This will be accomplished through structural correlation of amphotericin B with other polyene macrolide antibiotics and synthetic modification.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017595-06
Application #
3127295
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1980-12-01
Project End
1986-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Hartsel, S C; Perkins, W R; McGarvey, G J et al. (1988) A selective cholesterol-dependent induction of H+/OH- currents in phospholipid vesicles by amphotericin B. Biochemistry 27:2656-60