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.
Szpilman
Alex M
AM
Laboratorium für Organische Chemie der ETH-Zürich, HCI H 335, Wolfgang Pauli Strasse 10, 8093 Zurich, Switzerland.
Cereghetti
Damiano M
DM
Manthorpe
Jeffrey M
JM
Wurtz
Nicholas R
NR
Carreira
Erick M
EM
D000666:Amphotericin B / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D055592:Biophysical Phenomena; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry; D006595:Hexosamines / Q000737:chemistry*; D015394:Molecular Structure
D006027:Glycosides; D006595:Hexosamines; C017501:methylamphotericin B; C014692:mycosamine; D000666:Amphotericin B