Click Chemistry

on Feb 16th, 2011 at 09.36 am

Click chemistry is a chemical philosophy introduced by Sharpless in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining small units together. This is inspired by the fact that nature also generates substances by joining small modular units. Click chemistry (CC) can be summarized in one sentence: all searches must be restricted to molecules that are easy to make. Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations.

Classes of “Click” Reactions

  • Nucleophilic opening of highly strained rings:SN2 ring opening reactions,  Epoxides, aziridines, cyclic sulfates, cyclic sulfamidates, aziridinium
  • Ions:“Protecting Group” Reactions, Reversible carbonyl chemistry, Acetals, ketals and their aza-analogs
  • Cycloaddition Reactions:Hetero Diels-Alder, 1,3 dipolar cycloadditions involving heteroatoms

Advantages

  • It is very selective.Click Chemistry reaction takes place only between azide and alkyne components. It is does not interfere with most any other organic groups present in DNA and proteins backbone
  • There are no azides and alkynes in native biomolecules.These groups should be specially introduced into DNA and proteins. Alkyne-containing DNA can be prepared with alkyne phosphoramidite during standard oligo synthesis. Proteins labeled with azide and alkyne can be made using azide activated ester and alkyne activated ester.
  • Click Chemistry takes place in water.Aqueous DMSO, DMF, acetonitrile, alcohols, or pure water and buffers can be used for the reaction. The reaction is biocompatible and can take place in living cells.
  • Reaction is quick and quantitative.Click Chemistry is a tool that allows preparation of nanomols of conjugates in diluted solutions.
  • The reaction is pH-insensitive.Unlike reaction of NHS esters with amines, and some other conjugation chemistries, there is no need to control pH in reaction mixture. There is no need to add any special buffer, acid or base - Click Chemistry works well in pH interval of 4-11.
  • Click chemistry permits the labeling and detection of biological events that were previously impossible using standard methods.Click chemistry combines the specificity of antibodies with the flexibility of direct labeling, giving scientists new tools to probe into cellular function

Applications

Click chemistryapplications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA research, using bioconjugation reactions.

Recent success story for the click chemistry

It all happened with a click: In a search for histone deacetylase (HDAC) inhibitors using in situ click chemistry, the first example of protein–Cu acceleration of the azide–alkyne cycloaddition reaction was uncovered. The copper center in the protein target HDAC8 catalyzed triazole formation between one azide–alkyne pair among 30 possibilities. These results provide a new route to HDAC inhibitors and a precedent for new types of protein-based catalysts for click chemistry

(For more details)

Following Sharp-less visionary characterization of several idealized reactions as click reactions, the materials science and synthetic chemistry communities have pursued numerous routes toward the identification and implementation of these click reactions.