Friday, April 28, 2023

Hydrazonyl Sultones as Stable Tautomers of Highly Reactive Nitrile Imines for Fast Bioorthogonal Ligation Reaction

Ming Fang, Gangam Srikanth Kumar, Stefano Racioppi, Heyang Zhang, Johnathan D. Rabb, Eva Zurek, and Qing Lin

Journal of the American Chemical Society 2023

DOI: 10.1021/jacs.2c12325

Here we report the design and synthesis of a new class of bioorthogonal reagents called hydrazonyl sultones (HS) that serve as stable tautomers of highly reactive nitrile imines (NI). Compared to the photogenerated NI, HS display a broad range of aqueous stability and tunable reactivity in a 1,3-dipolar cycloaddition reaction, depending on substituents, sultone ring structure, and solvent conditions. DFT calculations have provided vital insights into the HS → NI tautomerism, including a base-mediated anionic tautomerization pathway and a small activation barrier. Comparative kinetic analysis of tetrazole vs HS-mediated cycloadditions reveals that a tiny fraction of the reactive NI (∼15 ppm) is present in the tautomeric mixture, underpinning the extraordinary stability of the six-membered HS. We further demonstrate the utilities of HS in selective modification of bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN)-lysine-containing nanobodies in phosphate buffered saline and fluorescent labeling of a BCN-lysine-encoded transmembrane glucagon receptor on live cells.



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