Synthesis of a Highly Water-Soluble Derivative of Amphotericin B with Attenuated Proinflammatory Activity
Adediran, Samusi A.
Day, Timothy P.
Kimbrell, Matthew R.
Warshakoon, Hemamali J.
Malladi, Subbalakshmi S.
David, Sunil A.
American Chemical Society
Scholarly/refereed, author accepted manuscript
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/mp9001602
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Amphotericin B (AmB), a well-known polyene antifungal agent displays a marked tendency to self-associate and, as a consequence, exhibits very poor solubility in water. The therapeutic index of AmB is low, and is associated with significant dose-related nephrotoxicity, as well as acute, infusion-related febrile reactions. Reports in the literature indicate that that toxicity of AmB may be related to the physical state of the drug. Reaction of AmB in dimethylformamide with bis(dimethylaminopropyl)carbodiimide yielded an unexpected N-alkylguanidine/N-acylurea bis-adduct of AmB which was highly water soluble. The absorption spectrum of the AmB derivative in water indicated excellent monomerization, and the anti-fungal activities of reference AmB and its water-soluble derivative against C. albicans were found to be virtually identical. Furthermore, the water-soluble adduct is significantly less active in engaging TLR4 which would suggest that the adduct may be less proinflammatory.
Adediran, S. A., Day, T. P., Sil, D., Kimbrell, M. R., Warshakoon, H. J., Malladi, S. S., & David, S. A. (2009). Synthesis of a Highly Water-Soluble Derivative of Amphotericin B with Attenuated Proinflammatory Activity. Molecular Pharmaceutics, 6(5), 1582–1590. http://doi.org/10.1021/mp9001602.
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