Bioorganic & Medicinal Chemistry 2015-09-01

Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane.

Tomoya Yamamoto, Yuichi Umegawa, Hiroshi Tsuchikawa, Nobuaki Matsumori, Shinya Hanashima, Michio Murata, Resul Haser, Bernard J Rawlings, Patrick Caffrey

Index: Bioorg. Med. Chem. 23 , 5782-8, (2015)

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Abstract

Amphotericin B (AmB) is a polyene macrolide antibiotic widely used to treat mycotic infections. In this paper, we focus on the role of the polyol moiety of AmB in sterol selectivity using 7-oxo-AmB, 7α-OH-AmB, and 7β-OH-AmB. The 7-OH analogs were prepared from 7-oxo-AmB. Their K(+) flux activity in liposomes showed that introduction of an additional ketone or hydroxy group on the polyol moiety reduces the original activity. Conformational analyses of these derivatives indicated that intramolecular hydrogen-bonding network possibly influenced the conformational rigidity of the macrolactone ring, and stabilized the active conformation in the membrane. Additionally, the flexible polyol leads to destabilization of the whole macrolactone ring conformation, resulting in a loss of sterol selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.