Structure-function studies on nucleoside antibiotic mureidomycin A: synthesis of 5 '-functionalised uridine models

The importance of functional groups in nucleoside antibiotic mureidomycin A (MRD A) for biological activity has been examined by derivatisation of sam ples of the natural product, and by synthesis of uridine-containing analogu es. N-Succinyl and di- and tri-acetyl derivatives MRD A have been prepared, and were found to have reduced activity as inhibitors of E. coli transloca se I. The enamide alkene of MRD A was found to be extremely resistant towar ds hydrogenation by a variety of reagents. Several 5'-functionalised uridin e derivatives were synthesised from N-3-p-methoxybenzyl-2',3'-isopropyliden euridine. A series of 5'-aminoacyl derivatives were prepared, and the 3-ami nopropionyl (IC50 260 mu M) and 7-aminoheptanoyl (IC50 1.5 mM) derivatives were found to act as reversible inhibitors. An analogue mimicking the carbo xy terminus of MRD A was synthesised, and also acted as an inhibitor of tra nslocase I (IC50 1.9 mM). A phosphonate analogue designed as a possible sui cide inhibitor showed modest inhibition (IC50 3.7 mM), which was shown to b e irreversible.