Strained cycloalkynes as new protein sulfenic acid traps

J Am Chem Soc. 2014 Apr 30;136(17):6167-70. doi: 10.1021/ja500364r. Epub 2014 Apr 16.


Protein sulfenic acids are formed by the reaction of biologically relevant reactive oxygen species with protein thiols. Sulfenic acid formation modulates the function of enzymes and transcription factors either directly or through the subsequent formation of protein disulfide bonds. Identifying the site, timing, and conditions of protein sulfenic acid formation remains crucial to understanding cellular redox regulation. Current methods for trapping and analyzing sulfenic acids involve the use of dimedone and other nucleophilic 1,3-dicarbonyl probes that form covalent adducts with cysteine-derived protein sulfenic acids. As a mechanistic alternative, the present study describes highly strained bicyclo[6.1.0]nonyne (BCN) derivatives as concerted traps of sulfenic acids. These strained cycloalkynes react efficiently with sulfenic acids in proteins and small molecules yielding stable alkenyl sulfoxide products at rates more than 100× greater than 1,3-dicarbonyl reagents enabling kinetic competition with physiological sulfur chemistry. Similar to the 1,3-dicarbonyl reagents, the BCN compounds distinguish the sulfenic acid oxoform from the thiol, disulfide, sulfinic acid, and S-nitrosated forms of cysteine while displaying an acceptable cell toxicity profile. The enhanced rates demonstrated by these strained alkynes identify them as new bioorthogonal probes that should facilitate the discovery of previously unknown sulfenic acid sites and their parent proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged Bicyclo Compounds / chemistry*
  • Cell Line
  • Cycloparaffins / chemistry*
  • Cysteine / analogs & derivatives*
  • Cysteine / analysis
  • Humans
  • Models, Molecular
  • Oxidation-Reduction
  • Proteins / chemistry*
  • Sulfenic Acids / analysis*


  • Bridged Bicyclo Compounds
  • Cycloparaffins
  • Proteins
  • Sulfenic Acids
  • bicyclo(6.1.0)nonyne
  • cysteinesulfenic acid
  • Cysteine