Metal‐Free Triazole Formation as a Tool for Bioconjugation

  title={Metal‐Free Triazole Formation as a Tool for Bioconjugation},
  author={S. van Berkel and A Ton J Dirks and Marjoke F. Debets and Floris L. van Delft and Jeroen J. L. M. Cornelissen and Roeland J. M. Nolte and F.P.J.T. Rutjes},
The development of selective and site-specific bio-orthogonal conjugation methods is an important topic in chemical biology. A wide range of methods, such as the Staudinger ligation, native chemical ligation, genetic incorporation, expressed-protein ligation, Huisgen azide–alkyne cycloaddition, and the Diels–Alder ligation are currently employed in the selective modification of proteins and other biomolecules. In recent years, the Cu-catalyzed variant of the Huisgen 1,3-dipolar cycloaddition… 

Application of Metal-Free Click Chemistry in Biological Studies

Three main metal-free click methodologies based on cycloaddition, Staudinger and thioene reactions are summarized and some mechanistic considerations and a collection of reagents that can be used in each method are contained.

A bioorthogonal ligation enabled by click cycloaddition of o-quinolinone quinone methide and vinyl thioether.

A new bioorthogonal ligation enabled by click hetero-Diels-Alder cycloaddition of in situ-generated o-quinolinone quinone methides and vinyl thioethers is reported, which is highly selective and proceeds smoothly under aqueous conditions.

Staudinger ligation as a method for bioconjugation.

The Staudinger ligation has set a high standard to which most of the new techniques in the emerging field of bio-orthogonal ligation strategies are often compared.

Traceless tosylhydrazone-based triazole formation: a metal-free alternative to strain-promoted azide-alkyne cycloaddition.

The suitability of this methodology as a strategy for metal-free triazole conjugation and an alternative to the traditional azide–alkyne cycloaddition is demonstrated.

Site-Specific Conjugation of Polymers to Proteins.

This article reviews the strategies for the site-specific synthesis of well-defined protein-polymer conjugates to provide a toolbox for the community and may provide useful cues in the areas of biotechnology, therapeutic drugs, and biomedicine.

The Diels-Alder reaction: A powerful tool for the design of drug delivery systems and biomaterials.

  • Manuel GregoritzaF. Brandl
  • Biology, Chemistry
    European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
  • 2015

A genetically encoded norbornene amino acid for the mild and selective modification of proteins in a copper-free click reaction.

This project shows that requirments for the incorporation of special unnatural amino acid into proteins to enable site-specific bioorthogonal functionalization can be met with a specially encoded norbornene amino acid which reacts selectively with nitrile imines.

Click Reactions: Azide‐Alkyne Cycloaddition

The term “Click-chemistry” is a general concept that describes reactions of enormous interest because of their unique characteristics for the synthetic chemistry. Many typical Click-reactions –among

Synthetic Strategies for the Biotinylation of Bioactive Small Molecules

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Progress in bioconjugation centered around cycloadditions of cyclic alkenes and alkynes have now established themselves as powerful tools in reagent-freeBioconjugations.



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Although it is sensitive to oxygen, the reliably efficient performance of the Cu.2 system makes it a useful tool for demanding bioconjugation applications.

A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems.

A strain-promoted [3 + 2] cycloaddition between cyclooctynes and azides that proceeds under physiological conditions without the need for a catalyst was demonstrated by selective modification of biomolecules in vitro and on living cells, with no apparent toxicity.

A comparative study of bioorthogonal reactions with azides.

Both the Staudinger ligation and the strain-promoted [3 + 2] cycloaddition using optimized cyclooctynes were effective for tagging azides on live cells and provided a guide for biologists in choosing a suitable ligation chemistry.

Diels-Alder ligation of peptides and proteins.

The results demonstrate that the Diels-Alder ligation offers an advantageous and technically straightforward new opportunity for the site-specific equipment of peptides and proteins with further functional groups and labels.

Bioconjugation by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition.

The copper-catalyzed cycloaddition reaction between azides and alkynes functions efficiently in aqueous solution in the presence of a tris(triazolyl)amine ligand to make rapid and reliable covalent connections to micromolar concentrations of protein decorated with either of the reactive moieties.

Synthesis of neoglycopolymers by a combination of "click chemistry" and living radical polymerization.

The synthesis of novel well-defined alkyne side chain functional polymers featuring narrow molecular weight distributions (PDI = 1.09-1.17) by living radical polymerization is described, providing an extremely powerful tool for the synthesis of libraries of materials that differ only in the nature of the sugar moiety presented on a well- defined polymer scaffold.

In situ click chemistry: enzyme inhibitors made to their own specifications.

Three new inhibitors were discovered, derived from tacrine and phenylphenanthridinium azides and acetylenes, in the reactions with Electrophorus electricus and mouse AChE, which include the newly formed triazole nexus as a significant pharmacophore.

Selective Staudinger Modification of Proteins Containing p‐Azidophenylalanine

It is shown that the Staudinger ligation can be used to modify this amino acid efficiently and selectively with spectroscopic probes in either proteins or phage-displayed peptides.

Site-specific polymer modification of therapeutic proteins.

Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides.

A novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported, and the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1, 3-dipoles entering the reaction.