Investigations into the decomposition of aminoacyl-substituted monosaccharide scaffolds from a drug discovery library

Organic & Biomolecular Chemistry
Q Q HeV Ferro

Abstract

This study investigated the unexpected decomposition and associated intermediates of compound 1, a specific member of a drug discovery library based on a monosaccharide scaffold. LC/MS and NMR spectroscopic analyses indicated that, under acidic conditions, 1 can be converted into the 4-aminogalactoside 2, due to cleavage of the 4-aminobutanoyl side chain. The reaction occurs most likely through an initial intramolecular amino–amide interaction, followed by an N- to O-acyl transfer of the side chain from C-4 to the C-6 position to form an ester intermediate (5), detectable by NMR, and subsequent hydrolysis. Similar decomposition reactions could be induced in selected compounds with similar structures, containing a free hydroxyl group at C-6 and a 4-aminobutanoyl side chain at C-4 of an aminogalactoside. Furthermore, three model compounds were synthesized without a C-6 hydroxyl group and with different length aminoalkanoyl side chains at the C-4 position. The model compounds all decomposed under acidic conditions, but at different rates and much slower when compared with compound 1, suggesting that both the C-6 hydroxyl group and the length of the side chain have an influence on stability.

References

Aug 21, 2003·Drug Discovery Today·Giang Thanh LeWim Meutermans
Sep 20, 2006·ChemMedChem·Wim MeutermansBernd Becker
Dec 8, 2009·The Journal of Organic Chemistry·Giang Le ThanhWim Meutermans
Oct 23, 2010·Organic Letters·Nathalie OllivierOleg Melnyk
Feb 23, 2011·Organic & Biomolecular Chemistry·Paul J Stevenson

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