Isolable Cysteine Sulfenyl Iodide: Stabilization by a Molecular Cradle, Crystal Structure, and Biologically Relevant...

Cysteine sulfenyl iodides (Cys-SIs) have long been recognized as important intermediates in the oxidative modification of cysteine thiols since 1950s, implicated in pathways such as hydrolysis to cysteine sulfenic acid (Cys-SOH) and electrophilic aromatic substitution with an indole ring of tryptophan to form Cys-Trp thioether linkages. Despite their proposed significance in both biological and chemical contexts, direct examination of Cys-SIs has been precluded by their intrinsic instability. Herein, the first isolation of a small-molecule Cys-SI, stabilized using a nanosized molecular cradle at the N-terminus of cysteine, is reported. The structure of the isolable Cys-SI is determined by X-ray crystallography, and its reactivity is investigated with a range of nucleophiles. Hydrolysis to Cys-SOH and reaction with an indole derivative provide direct chemical evidence for long-standing mechanistic proposals. Furthermore, rapid formation of sulfenamides with amines and high-yield adduct formation with dimedone, a canonical sulfenic-acid probe, reveal that Cys-SI possesses even greater electrophilicity than Cys-SOH. These results deliver a structurally defined reference for Cys-SI and inform mechanisms of iodine-mediated protein oxidation and peptide modification.