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Formation of hydrazones and stabilized boron-nitrogen heterocycles in aqueous solution from carbohydrazides and ortho-formylphenylboronic acids

Abstract

A recent addition to the suite of fast bioorthogonal reactions combines hydrazines and hydroxylamines with ortho-carbonyl substituted phenylboronic acids. Carbohydrazides are easily incorporated into biomolecules, making them appealing substrates in these reactions. Here we show that simple alkyl carbohydrazides form a single product with ortho-formylphenylboronic acid in organic solvent and in solid state. The solution structures of the products formed from the carbohydrazides in buffered aqueous solution, however, are markedly different than those identified in organic solvent and solid state. The reactants form a mixture of hydrazone and heterocylic products, the relative composition of which varies with pH. The observed reversibility of bioconguates using carbohydrazide can thus be explained by the reversibility of the boron-nitrogen bond in the heterocycle. In contrast, inclusion of an α-amine to the carbohydrazide substrate yields a single product in which both nitrogens are bonded to boron. These tricyclic structures are the same in organic solvent, solid state and aqueous solution from pH 4 to pH 9. Bioconjugates formed with α-amino carbohydrazides are stable to SDS-PAGE, while those formed with simple alkyl carboyhydrazides are not. We propose that inclusion of an intramolecular stabilizing ligand in a carbohydrazide substrate is a generally applicable principle that may be exploited to form boronic acid-based bioconjugates with defined structure and resistance to hydrolysis.

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Publication details

The article was received on 12 Jul 2017, accepted on 08 Aug 2017 and first published on 08 Aug 2017


Article type: Paper
DOI: 10.1039/C7OB01708A
Citation: Org. Biomol. Chem., 2017, Accepted Manuscript
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    Formation of hydrazones and stabilized boron-nitrogen heterocycles in aqueous solution from carbohydrazides and ortho-formylphenylboronic acids

    H. Gu, T. I. Chio, Z. Lei, R. J. Staples, J. S. Hirschi and S. Bane, Org. Biomol. Chem., 2017, Accepted Manuscript , DOI: 10.1039/C7OB01708A

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