Amphotericin B methyl ester

Amphotericin B is particularly effective against systemic infections caused by C. albicans and Cryptococcus neoformans. It is poorly absorbed from the gastrointestinal tract and is thus usually administered by intravenous injection under strict medical supervision. Amphotericin B methyl ester (Fig. 5.15C) is water-soluble, unlike amphotericin B itself, and can be administered intravenously as a solution. The two forms have equal antifungal activity but higher peak serum levels are obtained with the ester. Although the ester is claimed to be less toxic, neurological effects have been observed. An ascorbate salt has recently been described which is water-soluble, of similar activity and less toxic. 

Szlinder-Richert J, Cybulska B, Grzybowska J, Bolard J, Borowski E (2004) Interaction of amphotericin B and its low toxic derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester, with fungal, mammalian and bacterial cells measured by the energy transfer method. II Farmaco 59 289-296. 

Jordan and Seet studied the antiviral effects of Amphotericin B Methyl Ester (AME), an antimicrobial agent, on several vimses including VACV in a plaque reduction assay [64], The concentration of AME resulting in a 50% inactivation of the plaque forming units, after a 60 min exposure at 35°C, was reported to be 5.0 pg/mL. The authors suggested lipid components in the host cell membrane which incorporate into the viral envelope may serve as a susceptible site for AME. 

Antiviral effects of Amphotericin B Methyl Ester by a plaque reduction assay [64]). 

Jordan, G.W., and Seet, E.C., 1978. Antiviral effects of amphotericin B methyl ester. Antimicrob. Agents Chemother., 13 199-204. 

Etingov ED and Kholodova GV, Kul bakh VO and Kamatushkina AI, Acid-base properties of amphotericin B, Antibiotiki, 17, 301-305 (1972). "Titration of 66% aqueous dimethylformamide solutions of Amphotericin B with methanolic HCl and KOH yields pK s near 5.7 and 10.0. Comparison with N-acetyl-Amphotericin B (pK=6.5) and Amphotericin B-methyl ester (pK=8.8) assigns the two pK s to carboxyl and amino groups respectively. Amphotericin B is found to be almost completely zwitterionic in this solution (tautomeric equilibrium constant Kt = 1000 with respect to the neutral molecule)." S R... 

With all correct stereochemistries now set up, final deprotections and azido group reduction remained to be done in order to obtain the natural antibiotic. The route followed included desilylation, azide reduction, and isopropylidene removal leading to amphotericin B methyl ester which was saponified to the final natural antibiotic la. Both compounds were identical with authentic samples. 

Larson RK (1953) The mechanism of quinidine purpura. Blood 8 16-25 Little JR, Plut EJ, Kotler-Brajtburg J, Medoff G, Kobayashi GS (1978) Relationship between the antibiotic and immunoadjuvant effects of amphotericin B methyl ester. Im-munochemistry 15 219-224... 

The instability of polyenes should not be overstated the dry product is relatively stable and it has been shown that aqueous solutions of polyenes are stable at least for 24 h even when exposed to light, air and room temperatures [88—90]. When dissolved in aqueous systems, the antibiotic consists of a micellar dispersion held together by hydrophobic forces. This may confer a degree of protection in that the sensitive region of the antibiotic exists in a localised hydrophobic environment shielded from physical and chemical damage. When stored under identical conditions, dry amphotericin B and amphotericin B methyl ester exhibited similar stability. In aqueous solution, amphotericin B was more stable than its methyl ester. Spectrophotometric studies [91] have shown that in aqueous solutions amphotericin methyl ester was more dispersed than the parent compound and it appeared that increased water solubility was accompanied by increased vulnerability to damage [92]. 

Szpihnan AM, Cereghetti DM, Manthorpe JM, Wurtz NR, Caneira EM (2009) Synthesis and biophysical studies on 35-deoxy amphotericin B methyl ester. Chem Eur J 15 7117-7128... 

J. GrTybowska, P. Sowinski, J. Gumieniak, T. Zieniawa, and E. Borowski, -Methyl- -D-fructopyranosylamphotericin B methyl ester, new amphotericin B derivative of low toxicity, J. Antibiot., 50 (1997) 709-711. 

Chemical modification may considerably reduce the toxicity of polyenes. Amphotericin B methyl, ethyl, propyl or butyl esters have been shown to have LDso values ten times greater than that of the parent compound when intravenously injected into mice [396]. Similarly, the methyl to butyl esters of candi-cidin exhibited LD o values ten to forty times greater than that of candicidin when injected by the intraperitoneal route into mice [396]. 

Fig. 5.15 Antifimgal antibiotics A, griseofulvin B, nystatin C, amphotericin (R = H) and its methyl ester (R = CH3).

Amphotericin B is another related antifungal antibiotic. Its methyl ester is active against HSV-1 and -2, VV, SV and VSV with less cytotoxicity and improved water solubility [18]. 

The Zn-mediated alkyne addition was shown to proceed with excellent reagent control, as showcased by Carreira for the two advanced polyketide intermediates 314 and 315 (Scheme 2.40) [191]. Adduct 315 was further elaborated into the 35-deoxy aglycon 316 of the methyl ester derivative of the antifungal macrolide amphotericin B (317). 

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