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Issue 24, 2005
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The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase

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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 IC50 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.

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

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Article information


Submitted
22 Sep 2005
Accepted
24 Oct 2005
First published
15 Nov 2005

Org. Biomol. Chem., 2005,3, 4402-4411
Article type
Paper

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

C. M. Diaper, A. Sutherland, B. Pillai, M. N. G. James, P. Semchuk, J. S. Blanchard and J. C. Vederas, Org. Biomol. Chem., 2005, 3, 4402
DOI: 10.1039/B513409A

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