Click chemistry is a chemical philosophy introduced by K. Barry Sharpless of The Scripps Research Institute, in 2001[1][2] 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 mimicks nature.
The reactions in Click chemistry must (or would be desirable):
The process must (or would be desirable):
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In biological systems and biochemistry, proteins are made from repeating amino acid units and sugars are made from repeating monosaccharide units. The connecting units are based on carbon - hetero atom bonds C-X-C rather than carbon - carbon bonds. In addition, enzymes ensure that chemical processes can overcome large enthalpy hurdles by a series of reactions each requiring only a small energy step. Mimicking nature in organic synthesis is essential in the discovery of new pharmaceuticals given the large number of possible structures.
In 1996, Guida calculated the size of the pool of drug candidates at 1063, based on the presumption that a candidate consists of less than 30 non-hydrogen atoms, weighs less than 500 daltons, is made up of atoms of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine and bromine, and is stable at room temperature and stable towards oxygen and water.[3] Click chemistry in combination with combinatorial chemistry, high-throughput screening and building chemical libraries speeds up new drug discoveries by making each reaction in a multistep synthesis fast, efficient and predictable.
Many of the Click chemistry criteria are subjective; and even if measurable and objective criteria could be agreed upon, it's unlikely that any reaction will be perfect for every situation and application. However, several reactions have been identified which fit the concept better than others:
One of the most popular reactions within the click chemistry concept is the azide alkyne Huisgen cycloaddition using a Copper (Cu) catalyst at room temperature. It was discovered concurrently and independently by the groups of Valery V. Fokin and K. Barry Sharpless at the Scripps Research Institute in California[8] and Morten Meldal in the Carlsberg Laboratory, Denmark.[9] Although the Cu(I)-catalyzed variant was first reported by Meldal and co-workers for the synthesis of peptidotriazoles on solid support, these authors did not recognize the potential of the reaction and did not make a connection with the click chemistry concept. Fokin and Sharpless independently described it as a reliable catalytic process offering "an unprecedented level of selectivity, reliability, and scope for those organic synthesis endeavors which depend on the creation of covalent links between diverse building blocks", firmly placing it among the most reliable processes fitting the click criteria.
Copper and ruthenium are the commonly used catalysts in the reaction. The use of copper as a catalyst results in the formation of 1,4-regioisomer whereas ruthenium results in formation of the 1,5- regioisomer. [10] A disadvantage of the Cu catalysed click reaction is that it does not work on internal alkynes. A mechanism for this reaction was originally proposed based on theoretical calculations.[11]
Click chemistry has widespread applications. Some of them are:
Click chemistry also has been used for selectively labeling biomolecules within biological system. A click reaction that is to be performed in a living system needs to meet an even more rigorous set of criteria; it must be bioorthogonal, meaning the reagents used may not interact with the biological system in any way, nor may they be toxic. The reaction must also be carried out at neutral pH and at or around body temperature. Most click reactions have a high energy content which make the reactions irreversible and involve carbon-hetero atom bonding processes. An example of this is the Staudinger ligation of azides.
On July 15, 2010, it was announced that The Scripps Research Institute signed a license agreement with Allozyne, a privately held, Seattle based biotechnology company. The agreement with The Scripps Research Institute provides Allozyne with a license to apply Click chemistry for exclusive development in key therapeutic fields in addition to a non-exclusive license for diagnostic applications.
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