Open-chain thiamine analogues as potent inhibitors of thiamine pyrophosphate (TPP)-dependent enzymes

A common approach to studying thiamine pyrophosphate (TPP)-dependent enzymes is by chemical inhibition with thiamine/TPP analogues which feature a neutral aromatic ring in place of the positive thiazolium ring of TPP. These are potent inhibitors but their preparation generally involves multiple synt...

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Published inOrganic & biomolecular chemistry Vol. 21; no. 32; pp. 6531 - 6536
Main Authors Chan, Alex H. Y, Ho, Terence C. S, Leeper, Finian J
Format Journal Article
LanguageEnglish
Published CAMBRIDGE Royal Soc Chemistry 16.08.2023
Royal Society of Chemistry
Subjects
Aromatic compounds
Binding
Chemistry
Chemistry, Organic
Enzymes
Inhibitors
Physical Sciences
Pyruvic acid
Science & Technology
Thiamine
DESIGN
DERIVATIVES
EFFICIENCY
PYRUVATE-DEHYDROGENASE COMPLEX
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Summary:A common approach to studying thiamine pyrophosphate (TPP)-dependent enzymes is by chemical inhibition with thiamine/TPP analogues which feature a neutral aromatic ring in place of the positive thiazolium ring of TPP. These are potent inhibitors but their preparation generally involves multiple synthetic steps to construct the central ring. We report efficient syntheses of novel, open-chain thiamine analogues which potently inhibit TPP-dependent enzymes and are predicted to share the same binding mode as TPP. We also report some open-chain analogues that inhibit pyruvate dehydrogenase E1-subunit (PDH E1) and are predicted to occupy additional pockets in the enzyme other than the TPP-binding pockets. This opens up new possibilities for increasing the affinity and selectivity of the analogues for PDH, which is an established anti-cancer target. Flexible open-chain analogues of thiamine can occupy various different pockets in pyruvate dehydrogenase E1 subunit, depending on whether they have a metal-binding group or not.
Bibliography:Electronic supplementary information (ESI) available: Methods and results for enzyme assays and computational docking; synthetic methods, compound characterisation and NMR spectra. See DOI
https://doi.org/10.1039/d3ob00884c
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ISSN:1477-0520
1477-0539
DOI:10.1039/d3ob00884c