Molecular Umbrella−Amphotericin B Conjugates

ABSTRACT: A tetrawalled and an octawalled molecular umbrella conjugate of amphotericin B (AmB) have been synthesized. Both conjugates exhibit high water solubility, a low tendency to aggregate, negligible hemolytic activity at 100 μM, and an ability to release a derivative of AmB under reducing conditions that exhibits high antifungal activity. Whereas the larger, octawalled conjugate shows slight adsorption to liposomal membranes and an ability to cross them by passive transport, the tetrawalled analogue shows significant adsorption and much lower bilayer transport activity. The potential of molecular umbrella−AmB conjugates as therapeutic agents is briefly discussed. Amphotericin B (AmB) is an important antifungal agentthat has been used to treat systemic fungal infections for more than half a century.1−4 Although considerable effort has been made to understand its mechanism of action, the means by which this macrolide antibiotic destroys fungal cells remain a matter of debate. In the most popular model, several AmB molecules are thought to combine with ergosterol to for