Ultra-rapid Electrophilic Cysteine Arylation
Bradley M. Lipka, Daniel S. Honeycutt, Gregory M. Bassett, Taylor N. Kowal, Max Adamczyk, Zachary C. Cartnick, Vincent Betti, Jacob M. Goldberg, Fang Wang
Abstract
Rapid bond-forming reactions are crucial for efficient bioconjugation. We describe a simple and practical strategy for facilitating ultra-rapid electrophilic cysteine arylation. Using a variety of sulfone-activated pyridinium salts, this uncatalyzed reaction proceeds with exceptionally high rate constants, ranging from 9800 to 320,000 M –1 ·s –1, in pH 7.0 aqueous buffer at 25 °C. Such reactions allow for stoichiometric bioconjugation of micromolar cysteine within minutes or even seconds. Even though the arylation is extremely fast, the chemistry exhibits excellent selectivity, thus furnishing functionalized peptides and proteins with both high conversion and purity.