Recent developments in a variation of the classical aldehyde/ketone condensation based on <i>ortho</i>-carbonylphenylboronic acids have uncovered markedly accelerated rates compared to the simple carbonyl counterparts. The products of these reactions are distinct, often in the form of boron-nitrogen heterocycles. In particular, we have shown that the coupling of 2-formylphenylboronic acid (2fPBA) with an α-amino-hydrazide produces a unique zwitterionic and stable 2,3,1-benzodiazaborine derivative. The enhanced stability and hydrophilicity of this type of linkage is desirable for applications such as antibody-drug conjugates. We show that an antibody and a fluorophore (as payload) equipped with the relevant reactive handles undergo rapid conjugation at near-stoichiometric ratios, displaying a reaction half-life of only ~5 min with 2 equivalents of the linker-payload. Importantly, the ligation reaction occurs in complex environments, and the resulting conjugate is stable for days in human serum. This reaction is orthogonal to the popular tetrazine-<i>trans</i>-cyclooctene and the SPAAC-azide ligations, enabling access to more complex modalities. One illustration is the creation of a dual, site specifically labeled therapeutic antibody by simultaneous addition of reactive components.

Bioconjugation via zwitterionic boron-nitrogen heterocycles

2019 Fall National Meeting

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