Copper-Free Click Chemistry

By Vidhi Chauhan | 1 October 2024

Copper in Biological Systems

Copper is a trace mineral found in all body tissues. It Is required for the formation of red blood cells, iron absorption, neuron and immune function. It is also required as a cofactor for many enzymes, called cuproenzymes.

Copper Toxicity

Copper as a toxic metal affects the liver mainly. It usually results in the development of liver cirrhosis, and damage to organs such as the kidneys, the heart and the brain. When consumed through food, copper intoxicated food stuff can cause the development of acute gastrointestinal symptoms. Copper toxicity is also linked to Alzheimer’s disease, where free copper levels have been found to rise.

Copper Free Click Chemistry

Copper free click chemistry encompasses bioorthogonal reactions that do not use toxic copper catalysts and proceed at lower activation barriers. Bioorthogonal reactions are reactions which occur inside biological systems without interfering with the local reactions.

It is based on Wittig's copper free click reaction. It is a reaction between cyclooctyne and phenyl azide to produce a single product, a triazole, in an extremely fast reaction. The reaction moves forward due to the ring strain in the cyclooctyne. Ring strain refers to the instability arising due to differences in bond angles. The ideal bond angle for an alkyne is 180 degree, but cyclooctyne has an angle of 160 degree, which causes strain. Other derivatives of cyclooctyne that are used for copper free chemistry are OCT, MOFO (monofluorinated cyclooctyne), DIFO (difluorinated cyclooctyne) and MFCO (monofluorosubstituted cyclooctyne).

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Applications

Copper free click chemistry is used for labeling biomolecules in live laboratory mice. Mice are the model organism for understanding human biological systems due the similarities in their biology. It was successfully used to label molecules called azidosugars without any damage to tissues like intestines, heart and liver of the mice, due to copper toxicity. Particularly, copper free click chemistry presents a good option for facilitating clicking in Alzheimer's prone or Alzheimer's afflicted systems.

References

  1. Pamela V. Changa,1, Jennifer A. Preschera,1, Ellen M. Slettena , Jeremy M. Baskina , Isaac A. Millera , Nicholas J. Agarda , Anderson Loa , and Carolyn R. Bertozzi Copper-free click chemistry in living animals
  2. Lisa M. Gaetke, Ching Kuang Chow Copper toxicity, oxidative stress, and antioxidant nutrients
  3. Jeremy M. Baskin; Jennifer A. Prescher; Scott T. Laughlin; Nicholas J. Agard; Pamela V. Chang; Isaac A. Miller; Anderson Lo; Julian A. Codelli; Carolyn R. Bertozzi (2007). "Copper-free click chemistry for dynamic in vivo imaging". Proceedings of the National Academy of Sciences.
  4. Rostovtsev, VV, Green, LG, Fokin, VV, Sharpless, KB. (2002) Angew. Chem.. 114, 2596.
  5. Akeroyd N. (2010) Click chemistry for the preparation of advanced macromolecular architectures Stellenbosch University.
  6. Image: Sigma Aldrich

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