Issue 19, 2008

Synthesis and biological evaluation of pyrophosphate mimics of thiamine pyrophosphate based on a triazole scaffold

Abstract

Novel triazole-based pyrophosphate analogues of thiamine pyrophosphate (TPP) have been synthesised and tested for inhibition of pyruvate decarboxylase (PDC) from Zymomonas mobilis. The thiazolium ring of thiamine was replaced by a triazole in an efficient two-step procedure. Pyrophosphorylation then gave extremely potent triazole inhibitors with KI values down to 20 pM, compared to a KD value of 0.35 μM for TPP. This triazole scaffold was used for further investigation and six analogues containing mimics of the pyrophosphate group were synthesised and tested for inhibition of PDC. Several effective analogues were found with KI values down to around 1 nM.

Graphical abstract: Synthesis and biological evaluation of pyrophosphate mimics of thiamine pyrophosphate based on a triazole scaffold

Article information

Article type
Paper
Submitted
21 Apr 2008
Accepted
09 Jun 2008
First published
11 Jul 2008

Org. Biomol. Chem., 2008,6, 3561-3572

Synthesis and biological evaluation of pyrophosphate mimics of thiamine pyrophosphate based on a triazole scaffold

K. M. Erixon, C. L. Dabalos and F. J. Leeper, Org. Biomol. Chem., 2008, 6, 3561 DOI: 10.1039/B806580B

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