Assessment of chemoselective neoglycosylation methods using chlorambucil as a model

Randal D. Goff, Jon S. Thorson

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

To systematically assess the impact of glycosylation and the corresponding chemoselective linker upon the anticancer activity/selectivity of the drug chlorambucil, herein we report the synthesis and anticancer activities of a 63-member library of chlorambucil-based neoglycosides. A comparison of N-alkoxyamine-, N-acylhydrazine-, and N-hydroxyamine-based chemoselective glycosylation of chlorambucil revealed sugar- and linker-dependent partitioning among open- and closed-ring neoglycosides and corresponding sugar-dependent variant biological activity. Cumulatively, this study represents the first neoglycorandomization of a synthetic drug and expands our understanding of the impact of sugar structure upon product distribution/equilibria in the context of N-alkoxyamino-, N-hydroxyamino-, and N-acylhydrazine-based chemoselective glycosylation. This study also revealed several analogues with increased in vitro anticancer activity, most notably d-threoside 60 (NSC 748747), which displayed much broader tumor specificity and notably increased potency over the parent drug.

Original languageEnglish
Pages (from-to)8129-8139
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number22
DOIs
StatePublished - Nov 25 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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