Synthesis of a highly water-soluble derivative of amphotericin B with attenuated proinflammatory activity

Samusi A. Adediran, Timothy P. Day, Diptesh Sil, Matthew R. Kimbrell, Hemamali J. Warshakoon, Subbalakshmi S. Malladi, Sunil A. David

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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 the 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 antifungal activities of reference AmB and its water-soluble derivative against Candida 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.

Original languageEnglish (US)
Pages (from-to)1582-1590
Number of pages9
JournalMolecular pharmaceutics
Volume6
Issue number5
DOIs
StatePublished - Oct 5 2009

Keywords

  • Aggregation
  • Amphotericin B
  • Antifungal
  • Carbodiimide
  • Solubility
  • Toll-like receptors
  • Toxicity

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