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Oximes and Hydrazones in Bioconjugation: Mechanism and Catalysis
journal contribution
posted on 2017-06-22, 19:49 authored by Dominik
K. Kölmel, Eric T. KoolThe formation of
oximes and hydrazones is employed in numerous
scientific fields as a simple and versatile conjugation strategy.
This imine-forming reaction is applied in fields as diverse as polymer
chemistry, biomaterials and hydrogels, dynamic combinatorial chemistry,
organic synthesis, and chemical biology. Here we outline chemical
developments in this field, with special focus on the past ∼10
years of developments. Recent strategies for installing reactive carbonyl
groups and α-nucleophiles into biomolecules are described. The
basic chemical properties of reactants and products in this reaction
are then reviewed, with an eye to understanding the reaction’s
mechanism and how reactant structure controls rates and equilibria
in the process. Recent work that has uncovered structural features
and new mechanisms for speeding the reaction, sometimes by orders
of magnitude, is discussed. We describe recent studies that have identified
especially fast reacting aldehyde/ketone substrates and structural
effects that lead to rapid-reacting α-nucleophiles as well.
Among the most effective new strategies has been the development of
substituents near the reactive aldehyde group that either transfer
protons at the transition state or trap the initially formed tetrahedral
intermediates. In addition, the recent development of efficient nucleophilic
catalysts for the reaction is outlined, improving greatly upon aniline,
the classical catalyst for imine formation. A number of uses of such
second- and third-generation catalysts in bioconjugation and in cellular
applications are highlighted. While formation of hydrazone and oxime
has been traditionally regarded as being limited by slow rates, developments
in the past 5 years have resulted in completely overturning this limitation;
indeed, the reaction is now one of the fastest and most versatile
reactions available for conjugations of biomolecules and biomaterials.
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Keywords
imine formationα- nucleophilescombinatorial chemistry5 yearstransition statechemical propertiesconjugation strategytransfer protonschemical biologyRecent workoutline chemical developmentsreactant structure controls ratesrapid-reacting α- nucleophilesnucleophilic catalystsreactive aldehyde groupRecent strategiespolymer chemistrytetrahedral intermediatesimine-forming reactionreactive carbonyl groups
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