his article focus mainly on click chemistry mechanisms and its applications, click chemistry is an easy way to generate substances quickly and reliably by joining small units together, with this ease of use mechanism, click chemistry as found its applications in various technologies especially in drug discovery ,medicinal chemistry, enzyme activity, chemistry natural products, material science, polymers, nanotechnology and bioconjugation
APPLICATIONS OF CLICK
CHEMISTRY IN DRUG
Article written and published by
Click chemistry is a chemical philosophy introduced by K. Barry Sharpless
of The Scripps Research Institute, 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 is not a specific reaction; it is a
concept that mimics nature.
Click chemistry is a modular approach that uses only the most practical and
reliable chemical transformations. Its applications 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.
Numerous examples of click reactions have been reported for preparation
and functionalization of polymeric micelles and nanoparticles, liposomes
and polymersomes, capsules, microspheres, metal and silica
nanoparticles, carbon nanotubes and fullerenes, or bionanoparticles.
Among these click processes, Cu (I)-catalyzed azide-alkyne cycloaddition
(CuAAC) has attracted most attention based on its high
orthogonality, reliability and experimental simplicity for non-specialists. The
main aim of the write up is to focus on the importance of Click chemistry in
Taking cues from nature
Click chemistry is a chemical philosophy introduced by K Barry Sharpless of The
Scripps Research Institute, 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.
“Generating substances by joining small units together with heteroatom links (C-X-
C)“ is termed as Click Chemistry. The goal is to develop an expanding set of
powerful, selective, and modular „blocks‟ that work reliably in both small- and large-
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
being labeled, such as amino and carboxy groups.
Click Chemistry is a reaction between azide and alkyne yielding covalent product
triazole conjugate. This process is also known as CuAAC-Cu catalyzed alkyne azide
One of the most useful is the reaction between organic azides and
alkynes, catalyzed by Cu (I) compounds. This reaction is a [3+2] cycloaddition which
is highly specific, can be carried out in water and fully bioorthogonal. As a result, it
has rapidly established a prominent role in materials science, medicinal, and bio
Click chemistry applications
t is important to recognize that click reactions achieve
their required characteristics by having a high
thermodynamic driving force, usually greater than 20
Carbon-heteroatom bond forming reactions comprise
the most common examples, including the following
classes of chemical transformations.
Cycloadditions of unsaturated species, especially 1,3-
dipolar cycloaddition reactions, but also the Diels-
Alder family of transformations
Nucleophilic substitution chemistry, particularly ring-
opening reactions of strained heterocyclic
electrophiles such as epoxides, aziridines, aziridinium
ions, and episulfonium ions;
Click chemistry applications
Carbonyl chemistry of the “non-aldol” type, such as formation of
ureas, thioureas, aromatic heterocycles, oxime ethers, hydrazones, and
Additions to carbon-carbon multiple bonds, especially oxidative cases such
as epoxidation, dihydroxylation, aziridination, and sulfenyl halide
addition, but also Michael additions of Nu-H reactants
It describe reactions that are high yielding, wide in scope, create only
byproducts that can be removed without chromatography, are stereo
specific, simple to perform, and can be conducted in easily removable or
benign solvents. It was developed in parallel with the interest within the
pharmaceutical, materials, and other industries in capabilities for generating
large libraries of compounds for screening in discovery research.
Click chemistry is a newer approach to the synthesis of drug-like molecules
that can accelerate the drug discovery process by utilizing a few practical
and reliable reactions.
In the search for new drugs, the Click Chemistry started to give very
Click chemistry applications
Click chemistry has widespread applications.
Preparative organic synthesis of 1, 4-substituted triazoles
Modification of peptide function withTriazoles
Modification of natural products and pharmaceuticals
Click chemistry is being used increasingly in biomedical research, ranging from lead discovery
and optimization, to tagging of biological systems, such as proteins, nucleotides and whole
Macrocyclizations using Cu (I) catalyzed triazole couplings
Modification of DNA and nucleotides by triazole ligation
In Supramolecular chemistry
Carbohydrate clusters and carbohydrate conjugation by Cu(I) catalyzed triazole ligation reactions
More On Click Chemistry
Click chemistry has become a burgeoning strategy of
bioconjugation in the development of bifunctional molecules.
Bioconjugation involves the attachment of synthetic labels to
biomolecular building blocks, such as fusing two or more proteins
together or linking a carbohydrate with a peptide, and covers a wide
range of science between molecular biology and chemistry.
Although bioconjugation is applicable to the in vivo labeling of
biomolecules, only a handful of reactions are actually useful.
The possibility of applying click chemistry in bioconjugation was first
demonstrated by Tornoe et al. for the preparation of peptidotriazoles
via solid-state synthesis. Their goal was to develop new, more
efficient synthetic methods to prepare various [1,2,3]-triazole
pharmacophores for potential biologic targets. This initial report
makes possible the introduction of various novel functional and
reporter groups into biomolecules, such as peptides and
proteins, for DNA labeling and modification, and for cell-surface
More On Click Chemistry
Click chemistry continues to attract attention for the labeling of
proteins and live organisms. Wang et al. successfully labeled
Cowpea mosaic virus (CPMV) particles with fluorescein with >95%
yield. The labeling was performed by modifying the surface of viral
protein (either lysine or cysteine residues) with azides or
alkynes, followed by reaction with fluorescein-bearing
complementary groups. Similarly, Link and Tirrell were able to
modify Eschericia coli with an azide-bearing outer membrane
protein C (OmpC). The modified cell was then biotinylated by
reacting with a biotinalkyne derivative under copper-catalyzed click
Deiters et al. developed a method to genetically encode proteins of
Saccharomyces cerevisiae with azide- or acetylene-based synthetic
amino acids. The genetic modification was done by reacting an
alkyne- or an azide-bearing protein with the counterpart unnatural
amino acid. In the same study, the possibility of inserting organic
molecules to proteins by an azide-alkyne [3+2] cycloaddition
reaction was demonstrated by reacting azide- or alkyne-bearing
proteins with azide- or alkyne-bearing dyes.
Click chemistry has proven to be a powerful tool in
biomedical research, ranging from combinatorial
chemistry and target-templated in situ chemistry for
lead discovery, to bioconjugation strategies for
proteomics and DNA research et al.
It has become synonymous with the Huisgen 1, 3-
dipolar cycloaddition reaction and has gained potential
recognition in drug discovery.
Moving forwards, the technology will play an influential
role in the design of future drugs, owing to its
simplicity. Looking at the current market trends, one
can safely say that click chemistry can serve as a
promising route in drug discovery.
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