The unique reactivity of N-phenacyl-derived thiazolium salts toward α-dicarbonyl compounds

Rejuvenation Res. 2013 Feb;16(1):43-50. doi: 10.1089/rej.2012.1370.

Abstract

Advanced glycation end products (AGEs), a heterogeneous mixture of compounds formed by non-enzymatic chemical reactions between sugars and the nucleophilic residues of proteins, have been implicated in the pathogenesis of a number of diseases. ALT-711 is an N-phenacyl-derived thiazolium carbene developed as a therapeutic agent for cardiovascular diseases that is proposed to function through cleaving preformed AGE-protein crosslinks. However, despite promising results in animal models and clinical trials, its mechanism of action still remains controversial. Herein, we report the first systematic investigations into dicarbonyl cleavage by ALT-711. We demonstrate that it is capable of cleaving α-diketones more efficiently and likely via a distinct mechanism compared with other N-heterocyclic carbene precursors. We also show that ALT-711 reacts rapidly with α-keto aldehydes to form cyclic diol products, and it can efficiently scavenge methylglyoxal under physiological conditions to protect Escherichia coli from lethal concentrations of this reactive α-keto aldehyde. This work suggests ALT-711 may be especially suited for α-dicarbonyl clearance in vivo and supports a mode of action similar to that originally proposed. To this end, our findings may provide insights into the development of next-generation crosslink breakers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Ketones / chemistry*
  • Thiazoles / chemistry*

Substances

  • Ketones
  • Thiazoles