Synthesis of a highly water-soluble derivative of amphotericin B with attenuated proinflammatory activity.
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.
Adediran
Samusi A
SA
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, USA.
Day
Timothy P
TP
Sil
Diptesh
D
Kimbrell
Matthew R
MR
Warshakoon
Hemamali J
HJ
Malladi
Subbalakshmi S
SS
David
Sunil A
SA
D000666:Amphotericin B / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D002176:Candida albicans / Q000187:drug effects; D002460:Cell Line; D017930:Genes, Reporter; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D013053:Spectrophotometry; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014867:Water
D000935:Antifungal Agents; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014867:Water; D000666:Amphotericin B