Cybulska B, Gadomska I, Mazerski J, Cheron M, Bolard J
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdańsk, Poland.
Acta Biochim Pol. 2000;47(1):121-31.
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.
两性霉素B（AMB）的合理化学修饰导致了空间位阻AMB衍生物的合成。所选择的最佳化合物，N-甲基-N-D-果糖基两性霉素B甲酯（MF-AME）保留了母体抗生素的广谱抗真菌活性，并且在体内和体外对哺乳动物细胞的毒性低两个数量级。进行了MF-AME和AMB的比较研究，包括测定抗生素单体和自缔合形式的光谱性质、研究自缔合对人红细胞毒性的影响以及抗生素-甾醇相互作用。根据所得结果可以推测，MF-AME选择性毒性的提高部分可能是由于水性介质中水溶性低聚物浓度降低以及区分胆固醇和麦角固醇能力增强的结果。
