Single‐Molecule Observation of Intermediates in Bioorthogonal 2‐Cyanobenzothiazole Chemistry.

Qing, Yujia; Liu, Mira D.; Hartmann, Denis; Zhou, Linna; Ramsay, William J.; Bayley, Hagan

We report a single‐molecule mechanistic investigation into 2‐cyanobenzothiazole (CBT) chemistry within a protein nanoreactor. When simple thiols reacted reversibly with CBT, the thioimidate monoadduct was approximately 80‐fold longer‐lived than the tetrahedral bisadduct, with important implications for the design of molecular walkers. Irreversible condensation between CBT derivatives and N‐terminal cysteine residues has been established as a biocompatible reaction for site‐selective biomolecular labeling and imaging. During the reaction between CBT and aminothiols, we resolved two transient intermediates, the thioimidate and the cyclic precursor of the thiazoline product, and determined the rate constants associated with the stepwise condensation, thereby providing critical information for a variety of applications, including the covalent inhibition of protein targets and dynamic combinatorial chemistry.

COMBINATORIAL chemistry; CHEMISTRY; CYSTEINE; CLICK chemistry; DNA adducts; CONDENSATION; N-terminal residues

Angewandte Chemie, 2020, Vol 132, Issue 36, p15841

0044-8249

Academic Journal

10.1002/ange.202005729