Synthesis and anticandidal properties of polyoxin L analogues containing alpha-amino fatty acids.
Analogues of polyoxin L containing amino acids with saturated fatty acid like side chains were synthesized from the benzyloxycarbonyl-protected alpha-amino fatty acid p-nitrophenyl ester and uracil polyoxin C. Transfer hydrogenolysis using palladium black and formic acid gave diastereomeric, dipeptidyl polyoxin L analogues containing alpha-aminooctanoic acid (3), alpha-aminododecanoic acid (4), or alpha-aminohexadecanoic acid (5) as the amine terminal residue in 40-60% yield. Diastereomers of 3 and 5 were resolved by using high-performance liquid chromatography on a reversed-phase column and designated as 3a, 3b and 5a, 5b. Analogues 3-5 were excellent inhibitors of chitin synthetase from Candida albicans; 4, the best inhibitor, had an ID50 of 0.5 microM. The L,L diastereomers of 3 and 5 were 1-2 orders of magnitude more potent chitin synthetase inhibitors than their D,L homologues. None of the synthetic polyoxin L analogues inhibited transport of trimethionine, but 3a, 4, and 5b caused decreases of 71%, 87%, and 83%, respectively, in the initial rate of uptake of dileucine. Compounds 3-5 were significantly more stable to peptidase degradation than polyoxin L analogues containing naturally occurring alpha-amino acids. Compound 4 inhibited growth of C. albicans in culture at 40-80 micrograms/mL. All other analogues were less potent antifungals. The results suggest that synthetic polyoxins can be designed to have increased affinity for a peptide transport system and to have increased stability against intracellular degradation in C. albicans.
Khare
R K
RK
Department of Chemistry, College of Staten Island, City University of New York 10301.
Becker
J M
JM
Naider
F R
FR
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects*; D002687:Chitin Synthase / Q000037:antagonists & inhibitors; D002851:Chromatography, High Pressure Liquid; D005227:Fatty Acids / Q000032:analysis; D008826:Microbial Sensitivity Tests; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D005227:Fatty Acids; D011741:Pyrimidine Nucleosides; C039368:polyoxin L; D002687:Chitin Synthase