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Amphotericin B continues to be the drug of choice for the treatment of deep-seated fungal infections despite the usual accompaniment of severe toxic side-reaction and there has been considerable interest in recent years in developing a safer drug within this class of antibiotic1 • `8). We wish to report the synthesis of N-aminoacyl derivatives of polyene esters which appear to represent a significant advance in this area9). They are more water-soluble and less toxic than the parent polyenes, but retain their antifungal potency both in vitro9,10,11) and in vivo12) Our objective was the discovery of polyene derivatives that would form true solutions in water under physiological conditions, as we felt, as have others, that such derivatives would be less toxic and display different pharmacokinetics. Antibiotic 67-121-C13) (1), whose structure was established in our laboratories14), was the initial subject of our modification program. The N'-glycyl derivative (4) of antibiotic 67-121-C was prepared from the N'-iodoacetate (2) by treatment with aqueous ammonium hydroxide (Scheme 1). This compound was found to be slightly more potent than the parent antibiotic. This was particularly significant as simple N-acyl derivatives (e.g. N'-acetyl) of antibiotic 67-121-C and of other polyene antibiotics have all proved to be much less potent than the parent com-pounds15). Thus it was clear that at least one amino group was necessary for full antifungal potency to be retained. As derivatives of antibiotic 67-121-C were highly toxic, further studies were carried out on the non-aromatic heptaene, amphotericin B (5). Compounds in the Table were produced by acylating amphotericin B in dimethylsulfoxide (DMSO) with the active ester of the N-protected amino-acyl group. Esterification of the aglycone carboxylic acid group of the protected intermediate was achieved with the appropriate alkyl halide in excess, in the presence of a hindered tertiary amine or sodium carbonate. The chemical reactivity and solubility properties of the polyene antibiotics make stringent demands upon the nature of the chemical operations performed on them; the difficulty of purifying intermediates or products requires reactions to be very efficient and rapid. Our initial studies employed the trifluoroacetyl and the trichloroethoxycarbonyl blocking groups to protect the side-chain amino groups. Whilst the desired products could be, and indeed were, obtained, the conditions required for removing them did not meet the above criteria. The fluorenemethoxycarbonyl (Fmoc) protect-Scheme 1.

N-aminoacyl derivatives of polyene macrolide antibiotics and their esters.