ABSTRACT
The total synthesis of simpotentin (1), a new potentiator of amphotericin B activity against Candida albicans, was achieved. Our research results enabled the access of all stereoisomers of 1 and the elucidation of the unknown absolute configuration of 1. Furthermore, one of the stereoisomers is a better amphotericin B potentiator than 1 and is an excellent lead compound for the development of a novel amphotericin B potentiator.
Subject(s)
Amphotericin B/pharmacology , Mannosides/chemistry , Mannosides/pharmacology , Pyrans/chemical synthesis , Pyrans/pharmacology , Candida albicans/drug effects , Chemistry Techniques, Synthetic , Drug Synergism , Mannosides/chemical synthesis , Microbial Sensitivity Tests , Pyrans/chemistry , StereoisomerismABSTRACT
Simpotentin, a new potentiator of amphotericin B activity against Candida albicans and Cryptococcus neoformans, was isolated from the culture broth of Simplicillium minatense FKI-4981 by Diaion HP-20 column chromatography, centrifugal partition chromatography, and preparative HPLC. The structure of simpotentin was elucidated by spectroscopic analyses including NMR and MS. The compound has a mannose core to which two medium-chain fatty acids are linked. Simpotentin was found to potentiate amphotericin B activity against C. albicans by the microdilution method.
Subject(s)
Amphotericin B/pharmacology , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Candida albicans/drug effects , Drug Synergism , Hypocreales/metabolism , Antifungal Agents/chemistry , Candida albicans/growth & development , Chromatography/methods , Cryptococcus neoformans/drug effects , Cryptococcus neoformans/growth & development , Culture Media/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Microbial Sensitivity TestsABSTRACT
The targets of antifungal antibiotics in clinical use are more limited than those of antibacterial antibiotics. Therefore, new antifungal antibiotics with different mechanisms of action are desired. In the course of our screening for antifungal antibiotics of microbial origins, new antifungal antibiotics, simplifungin (1) and valsafungins A (2) and B (3), were isolated from cultures of the fungal strains Simplicillium minatense FKI-4981 and Valsaceae sp. FKH-53, respectively. The structures of 1 to 3 including their absolute stereochemistries were elucidated using various spectral analyses including NMR and collision-induced dissociation (CID)-MS/MS as well as chemical approaches including modifications to the Mosher's method. They were structurally related to myriocin. They inhibited the growth of yeast-like and zygomycetous fungi with MICs ranging between 0.125 and 8.0 µg/mL. An examination of their mechanisms of action by the newly established assay using LC-MS revealed that 1 and 2 inhibited serine palmitoyltransferase activity, which is involved in sphingolipid biosynthesis, with IC50 values of 224 and 24 nM, respectively.
