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

Abstract

The importance of functional groups in nucleoside antibiotic mureidomycin A (MRD A) for biological activity has been examined by derivatisation of samples of the natural product, and by synthesis of uridine-containing analogues. 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 translocase I. The enamide alkene of MRD A was found to be extremely resistant towards hydrogenation by a variety of reagents. Several 5′-functionalised uridine derivatives were synthesised from N  ³-p-methoxybenzyl-2′,3′-isopropylideneuridine. A series of 5′-aminoacyl derivatives were prepared, and the 3-aminopropionyl (IC₅₀ 260 µM) and 7-aminoheptanoyl (IC₅₀ 1.5 mM) derivatives were found to act as reversible inhibitors. An analogue mimicking the carboxy terminus of MRD A was synthesised, and also acted as an inhibitor of translocase I (IC₅₀ 1.9 mM). A phosphonate analogue designed as a possible suicide inhibitor showed modest inhibition (IC₅₀ 3.7 mM), which was shown to be irreversible.

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