N-Methyl-N-D-fructosyl amphotericin B methyl ester (MF-AME), a novel antifungal agent of low toxicity: monomer/micelle control over selective toxicity.
Rational chemical modification of amphotericin B (AMB) led to the synthesis of sterically hindered AMB derivatives. The selected optimal compound, N-methyl-N-D-fructosyl amphotericin B methyl ester (MF-AME) retains the broad spectrum of antifungal activity of the parent antibiotic, and exhibits a two orders of magnitude lower toxicity in vivo and in vitro against mammalian cells. Comparative studies of MF-AME and AMB comprising the determination of the spectroscopic properties of monomeric and self-associated forms of the antibiotics, the investigation of the influence of self-association on toxicity to human red blood cells, and of the antibiotic-sterol interaction were performed. On the basis of the results obtained it can be assumed that the improvement of the selective toxicity of MF-AME could in part be a consequence of the diminished concentration of water soluble oligomers in aqueous medium, and the better ability to differentiate between cholesterol and ergosterol.
Cybulska
B
B
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdańsk, Poland.
Gadomska
I
I
Mazerski
J
J
Borowski JGE
Cheron
M
M
Bolard
J
J
D000666:Amphotericin B / Q000031:analogs & derivatives / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D017136:Ion Transport; D007700:Kinetics; D008823:Micelles; D011188:Potassium / Q000378:metabolism; D013057:Spectrum Analysis
D000935:Antifungal Agents; D008823:Micelles; C108557:N-methyl-N-fructopyranosylamphotericin B methyl ester; D000666:Amphotericin B; D011188:Potassium