The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase

Christopher M. Diaper, Andrew Sutherland, Bindu Pillai, Michael N.G. James, Paul Semchuk, John S. Blanchard, John C. Vederas

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Aziridine analogues of diaminopimelic acid (DAP) have been prepared stereoselectively for the first time and evaluated as inhibitors of DAP epimerase. (2R,3S,3′S)-3-(3′-Aminopropane)aziridine-2,3′- dicarboxylate 4 was synthesised and shown to be a reversible inhibitor of DAP epimerase with an IC 50 value of 2.88 mM. (2S,4S)- and (2S,4R)-2-(4-Amino-4-carboxybutyl)aziridine-2-carboxylic acid (LL-azi-DAP 14 and DL-azi-DAP 29) were made as pure diastereomers, and both were shown to be irreversible inhibitors of DAP epimerase. LL-Azi-DAP 14 selectively binds to Cys-73 of the enzyme active site whereas DL-azi-DAP 29 binds to Cys-217 via attack of sulfhydryl on the methylene of the inhibitor aziridine ring. These observations are consistent with the two base mechanism proposed for the epimerisation of LL-DAP 1 and meso-DAP 2 by DAP epimerase.

Original languageEnglish (US)
Pages (from-to)4402-4411
Number of pages10
JournalOrganic and Biomolecular Chemistry
Volume3
Issue number24
DOIs
StatePublished - Dec 21 2005

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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