Organic Chemistry

Employing the suitable diazaborine chemistry in bioorthogonal applications

Authors

Abstract

Finding an ideal biorthogonal reaction that responds to a wide range of biological queries and applications is of great interest in biomedical applications. Rapid diazaborine (DAB) formation in water by the reactions of ortho-carbonyl phenylboronic acid with α-nucleophiles is an attractive conjugation module. Yet such reactions demand stringent criteria to satisfy biorthogonal applications. Here we show that widely used sulfonyl hydrazide (SHz) offers a stable DAB conjugate by combining with ortho-carbonyl phenylboronic acid at physiological pH, competent for an optimal biorthogonal reaction. The reaction conversion is quantitative and rapid (k2 >103 M-1s-1) at low micromolar concentrations, and it preserves comparable efficacy in a complex biological milieu. Further, DFT calculations support that SHz facilitated DAB formation runs via the lowest energy transition state and provides the most stable conjugate product while considering other biocompatible α-nucleophiles. This conjugation is extremely efficient on living cell surfaces, enabling compelling pretargeted imaging and peptide delivery. We anticipate this work will permit addressing a wide range of cell biology queries and drug discovery platforms exploiting commercially available sulfonyl hydrazide fluorophores and derivatives.

Content

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Supplementary material

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Employing the suitable diazaborine chemistry in bioorthogonal applications
All experimental data, NMR analysis. mass analysis, biological experiments.