Synthesis and biological evaluation of dipeptidyl and tripeptidyl polyoxin and nikkomycin analogs as anticandidal prodrugs

Abstract

Nine analogues (1-5, 9-12) of the peptidyl nucleoside antibiotics nikkomycin and polyoxin were synthesized and tested for their biological properties against different strains of the pathogenic yeast Candida albicans. The tripeptidyl series of analogues (1-5) was designed to behave as prodrugs, releasing a toxic moiety upon enzymatic hydrolysis inside the cell. The dipeptidyl series (9-12) was designed as double-targeted drugs, being themselves toxic and releasing a toxic amino acid upon hydrolysis. All the analogues were prepared by coupling suitably protected amino acid p-nitrophenyl esters to 1-(5'-amino-5'-deoxy-alpha-D-allofuranuronosyl)uracil (UPOC) or the corresponding polyoxins and nikkomycins, with subsequent removal of the protecting group. Improved coupling yields were observed when DMSO was used as the solvent. Products were purified with use of reversed-phase HPLC and, in one case, diastereomeric products (compound 11) were resolved by using this procedure. One of the tripeptidyl nikkomycins behaved as a prodrug but none of the compounds, as measured by in vitro testing, proved more effective than nikkomycin as an anticandidal agent.