Synthesis and Biophysical Studies on 35-Deoxy Amphotericin B Methyl Ester

The use of molecular editing in the elucidation of the mechanism of action of amphotericin B is presented. A modular strategy for the synthesis of amphotericin B and its designed analogues is developed, which relies on an efficient gram‐scale synthesis of various subunits of amphotericin B. A novel method for the coupling of the mycosamine to the aglycone was identified. The implementation of the approach has enabled the preparation of 35‐deoxy amphotericin B methyl ester. Investigation of the antifungal activity and efflux‐inducing ability of this amphotericin B congener provided new clues to the role of the 35‐hydroxy group and is consistent with the involvement of double barrel ion channels in causing electrolyte efflux. A modular strategy for the efficient assembly of amphotericin B analogues bearing modifications in the macrolactone ring is presented. The strategy relies on the efficient gram‐scale preparation of all the subunits of amphotericin B. Synthesis and biophysical studies on 35‐deoxy ampphotericin B provide new clues to the mode of action of amphotericin B.