Design of anticandidal agents: synthesis and biological properties of analogues of polyoxin L.
Six analogues of polyoxin L were synthesized from uridine. All of these analogues inhibited chitin synthetase from Candida albicans. Derivatization of the amine terminus of the polyoxin analogues resulted in loss of activity, and analogues containing aromatic amino acid residues were the most efficient inhibitors of chitin synthetase. The concentration of tryptophanyl uracil polyoxin C, 8, which caused 50% inhibition of chitin synthetase activity, was 1.6 X 10(-6) M. This was virtually identical with the activity found for polyoxin D. None of the inhibitors effectively competed with the entry of (Met)3 into C. albicans. All of the analogues caused severe morphological distortions of the yeast in culture, and a number of analogues killed C. albicans at millimolar concentrations. The results suggest that chitin synthetase inhibitors may have potential as anticandidal drugs.
D000935:Antifungal Agents / Q000138:chemical synthesis*; D002176:Candida albicans / Q000187:drug effects*; D002687:Chitin Synthase / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D009904:Optical Rotation; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000633:toxicity; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D011741:Pyrimidine Nucleosides; C039368:polyoxin L; C002458:polyoxorim; D002687:Chitin Synthase