N-Methyl-N-D-fructosyl amphotericin B methyl ester (MF-AME), a novel antifungal agent of low toxicity: Monomer/micelle control over selective toxicity.
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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.
- 1. Brajtburg, J., Powderly, W.G., Kobayashi, G.S. & Medoff, G. (1990) Amphotericin B, current understanding of mechanism of action. Antimicrob. Agents Chemother. 34, 183-188.
- 2. Bolard, J., Legrand, P., Heitz, F. & Cybulska, B. (1991) One-sided action of amphotericin B on cholesterol-containing membranes is determined by its self-association in the medium. Biochemistry 30, 5707-5715.
- 3. Mazerski, J., Bolard, J. & Borowski, E. (1982) Self-association of some polyene macrolide antibiotics in aqueous media. Biochim. Biophys. Acta 719, 11-17.
- 4. Mazerski, J., Bolard, J. & Borowski, E. (1995) Effect of the modifications of ionizable groups of amphotericin B on its ability to form complexes with sterols in hydroalcoholic media. Biochim. Biophys. Acta 1236, 170-176.
- 5. Cheron, M., Cybulska, B., Mazerski, J., Grzybowska, J., Czerwinski, A. & Borowski, E. (1988) Quantitative structure-activity relationships in amphotericin B derivatives. Biochem. Pharmacol. 37, 827-836.
- 6. Yamashita, K., Janout, V., Bernard, E.M., Armstrong, D. & Regen, S. (1995) Micelle/ monomer control over the membrane-disrupting properties of amphiphilic antibiotic. J. Am. Chem. Soc. 117, 6249-6253.
- 7. Grzybowska, J., Sowiński, P., Gumieniak, J., Zieniawa, T. & Borowski, E. (1997) N-Methyl- N-D-fructopyranosyl amphotericin B methyl ester, new amphotericin B derivative of low toxicity. J. Antibiot. 50, 709-711.
- 8. Legrand, P., Romero, E.A., Cohen, B.E. & Bolard, J. (1992) Effects of aggregation and solvent on the toxicity of amphotericin B to human erythrocytes. Antimicrob. Agents Chemother. 36, 2518-2522.
- 9. Gaboriau, F., Cheron, M., Petit, C. & Bolard, J. (1997) Heat-induced superaggregation of amphotericin B reduces its in vitro toxicity: A new way to improve its therapeutic index. Antimicrob. Agents Chemother. 41, 2345- 2351.
- 10. Gaboriau, F., Cheron, M., Leroy, L. & Bolard, J. (1997) Physico-chemical properties of the heat-induced superaggregates' of amphotericin B. Biophys. Chem. 66, 1-12.
- 11. Legrand, P., Cheron, M., Leroy, L. & Bolard, J. (1997) Release of amphotericin B from delivery system and its action against fungal and mammalian cells. J. Drug Target 4, 311-319.
- 12. Cybulska, B., Herve, M., Borowski, E. & Gary-Bobo, C.M. (1985) Effect of the polar head structure of polyene macrolide antifungal antibiotics on the mode of permeabilization of ergosterol-and cholesterol-containing lipidic vesicles studied by 31P-NMR. Molec. Pharmacol. 29, 293-298.
- 13. Herve, M., Debouzy, J.C., Borowski, E., Cybulska, B. & Gary-Bobo, C.M. (1989) The role of the carboxyl and amino groups of polyene macrolides in their interactions with sterols and their selective toxicity. A 31P-NMR study. Biochim. Biophys. Acta 980, 261-272.
- 14. Herve, M., Cybulska, B. & Gary-Bobo, C.M. (1985) Cation permeability induced by valinomycin, gramicidin D and amphotericin B in large lipidic unilamellar vesicles studied by 31P-NMR. Eur. Biophys. J. 12, 121-128.
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