Abstract
Mono- and disubstituted novel derivatives of the heptaene nystatin analog 28,29-didehydronystatin A1 (S44HP, 1) were obtained by chemical modification of the exocyclic C-16 carboxyl and/or an amino group of mycosamine moiety. The strategy of preparation of mono- and double-modified polyene macrolides was based on the use of intermediate hydrophobic N-Fmoc (9-fluorenylmethoxycarbonyl) derivatives that facilitated the procedures of isolation and purification of new compounds. The antifungal activity of the new derivatives was first tested in vitro against yeasts and filamentous fungi, allowing the selection of the most active compounds that were subsequently tested for acute toxicity in mice. 2-(N,N-dimethylamino)ethylamide of 1 (2) and 2-(N,N-dimethylamino)ethylamide of N-fructopyranosyl-28,29-didehydronystatin A1 (2a) were then selected for further evaluation in a mouse model of disseminated candidosis, and showed high efficacy while being considerably less toxic than amphotericin B (AmB). The compound with improved water solubility (2G, L-glutamic acid salt of 2) showed better chemotherapeutic activity than AmB in the mouse model of candidosis sepsis on a leucopenic background. Very low antifungal effect was seen after treatment with AmB, even if it was used in maximum tolerated dose (2 mg kg−1). Unlike AmB, compound 2G exhibited high activity in doses from 0.4 up to 4.0 mg kg−1, despite leucopenic conditions.
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References
Demain, A. L. & Sanchez, S. Microbial drug discovery: 80 years of progress. J. Antibiot. 62, 5–16 (2009).
De Kruijff, B. & Demel, R. A. Polyene antibiotic-sterol interactions in membranes of Acholeplasma laidlawii cells and lecithin liposomes. 3. Molecular structure of the polyene antibiotic-cholesterol complexes. Biochim. Biophys. Acta. 339, 57–70 (1974).
Ha̧c-Wydro, K., Dynarowicz-Ła̧tka, P., Grzybowska, J. & Borowski, E. N-(1-piperidinepropionyl)amphotericin B methyl ester (PAME)—a new derivative of the antifungal antibiotic amphotericin B: searching for the mechanism of its reduced toxicity. J. Colloid Interface Sci. 287, 476–484 (2005).
Slisz, M., Cybulska, B., Mazerski, J., Grzybowska, J. & Borowski, E. Studies of the effects of antifungal cationic derivatives of amphotericin B human erythrocytes. J. Antibiot. 57, 669–678 (2004).
Grzybowska, J., Sowinski, P., Gumieniak, J., Zieniawa, T. & Borowski, E. N-methyl-N-D-fructosyl amphotericin B methyl ester, new amphotericin B derivative of low toxicity. J. Antibiot. 50, 709–711 (1997).
Kazanah, N. & Hamann, M. T. SPK-843 new antifungal agent. Curr. Opin. Investig. Drugs 6, 845–856 (2005).
Bruheim, P. et al. Chemical diversity of polyene macrolides produced by Streptomyces noursei ATCC 11455 and recombinant strain ERD44 with genetically altered polyketide synthase NysC. Antimicrob. Agents Chemother. 48, 4120–4129 (2004).
Preobrazhenskaya, M. N. et al. Chemical modification and biological evaluation of new semi-synthetic derivatives of 28, 29-didehydronystatin A1 (S44HP), a genetically engineered anti-fungal polyene macrolide antibiotic. J. Med. Chem. 52, 189–196 (2009).
Takemoto, K., Yamamoto, Y. & Ueda, Y. Evaluation of antifungial pharmacodinamic characteristics of ambisome against Candida albicans. Microbiol. Immunol. 50, 579–586 (2006).
Acknowledgements
This study was supported by the Biosergen AS and the Research Council of Norway. We thank H Sletta and K Degnes for providing polyene macrolide 1 (S44HP). We thank Rohn and Haas France SAS company and personally IV Bakhtin for the present of a sample of Amberlite IRA743, TA Loim (Moscow) for excellent technical assistance in the purification of the compounds, NM Maliutina (Moscow) for HPLC analysis and Dr YN Luzikov (Moscow) for NMR spectra.
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Preobrazhenskaya, M., Olsufyeva, E., Tevyashova, A. et al. Synthesis and study of the antifungal activity of new mono- and disubstituted derivatives of a genetically engineered polyene antibiotic 28,29-didehydronystatin A1 (S44HP). J Antibiot 63, 55–64 (2010). https://doi.org/10.1038/ja.2009.118
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DOI: https://doi.org/10.1038/ja.2009.118
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