Interactive Bioconjugation at <i>N</i>‐Terminal Cysteines by Using <i>O</i>‐Salicylaldehyde Esters towards Dual Site‐Selective Functionalization

Silva, Maria J. S. A.; Faustino, Hélio; Cavadas, Rafaela; Veiros, Luı́s F.; Góis, Pedro M. P.

doi:10.1002/chem.202202377

Cited by 6 publications

(2 citation statements)

References 27 publications

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“…While numerous strategies are reported to selectively modify cysteines in complex biomolecules, only a few methods exist that are in principle reversible. [19][20][21][22][23][24][25][26] In order to provide a single reaction system that combines both prospects, irreversible clicking and reversible de-/trans-clicking, we sought to develop a new click transformation.…”

Section: Tetex: a Reversible Click Reactionmentioning

confidence: 99%

Click'n lock: Rapid exchange between asymmetric tetrazines and thiols enables reversible, chemoselective clicking and on demand locking

Gavriel

Doeselaar

Geers

et al. 2023

Preprint

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The late-stage functionalization and diversification of complex structures including biomolecules is often achieved with the help of click chemistry. Besides employing irreversible click-like reactions, many synthetic applications benefit from reversible clicking strategies, so called de-/trans-click approaches. Yet, the combination of both, reversible and irreversible click chemistry – while still respecting the stringent criteria of click transformations – remains so far elusive for modifications of high value structures. Here, we report click’n lock as a concept that enables reversible clicking and on-demand locking of chemical entities, thus switching from reversible to irreversible modifications of complex (bio)molecules. For this purpose, we employ the tetrazine – thiol exchange (TeTEx) reaction as a fully traceless click reaction with second order rate constants k2 up to 25 M-1 s-1 within aqueous environments. Employing TeTEx as a reversible click reaction for the chemoselective modification of biomolecules is made possible by the use of asymmetric 3,6-tetrazines bearing a single sulfide residue. The inherent reactivity of tetrazines towards inverse electron demand Diels – Alder (IEDDA) reactions allows to stabilize the clicked structure, switching from reversible to irreversible systems (click’n lock).

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Section: Tetex: a Reversible Click Reactionmentioning

confidence: 99%

Click'n lock: Rapid exchange between asymmetric tetrazines and thiols enables reversible, chemoselective clicking and on demand locking

Gavriel

Doeselaar

Geers

et al. 2023

Preprint

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show abstract

“…Several electrophilic groups were developed to selectively target proteins with N-terminal Cys, − e.g., thioesters, O -salicylaldehyde esters, activated aldehydes, activated nitriles, 2-((alkylthio)(aryl)methylene)malononitriles, N -hydroxysuccinimide-activated acrylamides, 2-benzylacrylaldehydes, 2-formylphenylboronic acids, − and monosubstituted cyclopropenones . Here, we focused on activated heteroaromatic nitriles, which were found to have a wide range of applicability in recent years. ,− Inspired by the final step in the biosynthesis of d -luciferin, Rao and co-workers utilized a click reaction between 2-cyanobenzothiazole and N-terminal Cys for protein labeling .…”

Section: Introductionmentioning

confidence: 99%

Tunable Heteroaromatic Nitriles for Selective Bioorthogonal Click Reaction with Cysteine

et al. 2023

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The binucleophilic properties of 1,2-aminothiol and its rare occurrence in nature make it a useful reporter for tracking molecules in living systems. The 1,2-aminothiol moiety is present in cysteine, which is a substrate for a biocompatible click reaction with heteroaromatic nitriles. Despite the wide range of applications for this reaction, the scope of nitrile substrates has been explored only to a limited extent. In this study, we expand the chemical space of heteroaromatic nitriles for bioconjugation under physiologically relevant conditions. We systematically assembled a library of 116 2-cyanobenzimidazoles, 1-methyl-2cyanobenzimidazoles, 2-cyanobenzothiazoles, and 2-cyanobenzoxazoles containing electron-donating and electron-withdrawing substituents at all positions of the benzene ring. The compounds were evaluated for their stability, reactivity, and selectivity toward the N-terminal cysteine of model oligopeptides. In comparison to the benchmark 6-hydroxy-2-cyanobenzothiazole or 6-amino-2cyanobenzothiazole, we provide highly selective and moderately reactive nitriles as well as highly reactive yet less selective analogs with a variety of enabling attachment chemistries to aid future applications in bioconjugation, chemical biology, and nanomaterial science.

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Interactive Bioconjugation at N‐Terminal Cysteines by Using O‐Salicylaldehyde Esters towards Dual Site‐Selective Functionalization

Silva

Faustino

Cavadas

et al. 2022

Chemistry A European J

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N-terminal Cys modification has been intensively studied to produce homogeneous bioconjugates essentially through two modes of reaction: reversible modification with the equilibrium shifted towards the formation of the desired conjugate or stable and irreversible conjugates. Herein, we report a new method of N-terminal cysteine modification using O-salicylaldehyde esters (OSAEs) through fast conjugation and irreversible deconjugation. These reagents can rapidly react with N-terminal Cys at low-micromolar concen-tration to form thiazolidines with subsequent hydrolysis of the ester moiety to the phenolic derivative. These phenolic thiazolidines can be hydrolyzed at acidic pH ( � 4.5) to recover the intact N-terminal Cys. Bioconjugation reactions using OSAEs offer controlled reversibility to as act as a protecting group for N-terminal cysteines, allowing the modification of in-chain residues without perturbing the N-terminal Cys, which can then be deprotected and used as a conjugation site.

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Interactive Bioconjugation at N‐Terminal Cysteines by Using O‐Salicylaldehyde Esters towards Dual Site‐Selective Functionalization

Cited by 6 publications

References 27 publications

Click'n lock: Rapid exchange between asymmetric tetrazines and thiols enables reversible, chemoselective clicking and on demand locking

Click'n lock: Rapid exchange between asymmetric tetrazines and thiols enables reversible, chemoselective clicking and on demand locking

Tunable Heteroaromatic Nitriles for Selective Bioorthogonal Click Reaction with Cysteine

Interactive Bioconjugation at N‐Terminal Cysteines by Using O‐Salicylaldehyde Esters towards Dual Site‐Selective Functionalization

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