Synthesis and biological evaluation of pyrophosphate mimics of thiamine pyrophosphate based on a triazole scaffold.
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 K(I) values down to 20 pM, compared to a K(D) value of 0.35 microM 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 K(I) values down to around 1 nM.
Erixon
Karl M
KM
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Dabalos
Chester L
CL
Leeper
Finian J
FJ
D011756:Diphosphates / Q000138:chemical synthesis / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011767:Pyruvate Decarboxylase / Q000037:antagonists & inhibitors*; D013835:Thiamine Pyrophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry*; D017355:Zymomonas / Q000201:enzymology*
D011756:Diphosphates; D004791:Enzyme Inhibitors; D014230:Triazoles; D011767:Pyruvate Decarboxylase; D013835:Thiamine Pyrophosphate