Bioorthogonal chemical reactions
have emerged as convenient and
rapid methods for incorporating
unnatural functionality into living systems. Different prototype reactions
have been optimized for use in biological settings. Optimization of
3 + 2 dipolar cycloadditions involving nitrones has resulted in highly
efficient reaction conditions for bioorthogonal chemistry. Through
substitution at the nitrone carbon or nitrogen atom, stereoelectronic
tuning of the reactivity of the dipole has assisted in optimizing
reactivity. Nitrones have been shown to react rapidly with cyclooctynes
with bimolecular rate constants approaching k
2 = 102 M–1 s–1, which are among the fastest bioorthogonal reactions reported (McKay
et al. Org. Biomol. Chem.
2012, 10, 3066–3070). Nitrones have also been shown to
react with trans-cyclooctenes (TCO) in strain-promoted
TCO-nitrone cycloadditions reactions. Copper catalyzed reactions involving
alkynes and nitrones have also been optimized for applications in
biology. This review provides a comprehensive accounting of the different
bioorthogonal reactions that have been developed using nitrones as
versatile reactants, and provides some recent examples of applications
for probing biological systems.
Trans‐cyclooctenes (TCOs) represent interesting and highly reactive dipolarophiles for organic transformations including bioorthogonal chemistry. Herein we show that TCOs react rapidly with nitrones and that these reactions are bioorthogonal. Kinetic analysis of acyclic and cyclic nitrones with strained‐trans‐cyclooctene (s‐TCO) shows fast reactivity and demonstrates the utility of this cycloaddition reaction for bioorthogonal labelling. Labelling of the bacterial peptidoglycan layer with unnatural d‐amino acids tagged with nitrones and s‐TCO‐Alexa488 is demonstrated. These new findings expand the bioorthogonal toolbox, and allow TCO reagents to be used in bioorthogonal applications beyond tetrazine ligations for the first time and open up new avenues for bioorthogonal ligations with diverse nitrone reactants.
Catalysts possessing sufficient activity to achieve intermolecular alkene hydroaminations under mild conditions are rare, and this likely accounts for the scarcity of asymmetric variants of this reaction. Herein, highly diastereoselective hydroaminations of allylic amines utilizing hydroxylamines as reagents and formaldehyde as catalyst are reported. This catalyst induces temporary intramolecularity, which results in high rate accelerations, and high diastereocontrol with either chiral allylic amines or chiral hydroxylamines. The reaction scope includes internal alkenes. Overall this work provides a new, stereocontrolled route to form complex vicinal diamines.
Nucleoside
analogs have proven effective for the inhibition of
viral polymerases and are the foundation of many antiviral therapies.
In this work, the antiretroviral potential of 6-azauracil analogs
was assessed using activity-based protein profiling techniques and
functional assays. Probes based on the 6-azauracil scaffold were examined
and found to bind to HCV polymerase and HIV-1 reverse transcriptase
through covalent modification of residues near the active site. The
modified sites on the HIV-1 RT were examined using a mass spectrometry
approach, and it was discovered that the azauracil moieties modified
the enzyme in proximity to its active site. However, these scaffolds
gave little or no inhibition of enzyme activity. Instead, a bifunctional
inhibitor was prepared using click chemistry to link the 6-azauracil
moiety to azidothymidine (AzT) and the corresponding triphosphate
(AzTTP). These bifunctional inhibitors were found to have potent inhibitory
function through a mode of action that includes both alkylation and
chain termination. An in vitro assay demonstrated that the bifunctional
inhibitor was 23-fold more effective in inhibiting HIV-1 RT activity
than the parent AzTTP. The bifunctional inhibitor was also tested
in HIV-1 permissive T cells where it decreased Gag expression similarly
to the front-line drug Efavirenz with no evidence of cytotoxicity.
This new bifunctional scaffold represents an interesting tool for
inhibiting HIV-1 by covalently anchoring a chain-terminating nucleoside
analog in the active site of the reverse transcriptase, preventing
its removal and abolishing enzymatic activity, and represents a novel
mode of action for inhibiting polymerases including reverse transcriptases.
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