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Chemistry click: making the difficult easy


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Diario de Navarra

Carlos Aydillo and Carmen Sanmartín

Professors of the department of Technology and Chemistry Pharmaceuticals of the School of Pharmacy and Nutrition

Among the many objectives of chemists is the development of new, increasingly complicated and specific molecules that can mimic natural molecules with medicinal properties. The construction of these molecules involves an enormous challenge . The organic synthesis of biomolecules is always complex, mainly due to the presence of multiple functional groups that can lead to undesired reactions, decreasing yields, leading to an increase in the complexity of the synthetic design and increasing costs in time and money.

The contributions of the winners of the award Nobel Prize at Chemistry 2022 respond to this problem. With Chemistry click, a term coined in 2000 by the Nobel laureate Barry Sharpless, very complex molecules can be built by simple reactions. This is possible through the development of simple, fast reactions with high performing and no side products. Shortly thereafter, Meldal and Sharpless himself independently discovered what is considered the Holy Grail of the Chemistry click: copper-catalyzed Huisgen azide-alkyne cycloaddition . The incorporation of an alkyne functional group into one molecule and an azide into another allows the joining of these two molecules, however complex they may be, in a straightforward manner. Among the uses of this reaction are the development of drugs, DNA mapping and the creation of materials with improved properties.

Later, Carolyn Bertozzi demonstrated that the same Huisgen cycloaddition reaction can be performed without copper as a catalyst, which is an improvement towards the green Chemistry . This reaction could be employed inside living organisms. Specifically, it mapped biomolecules present on the cell surface without affecting their chemical environment. Bertozzi introduced in 2008 the term "bioorthogonal reactions" as reactions between functional groups so selective to each other that they can be linked in a highly functionalized biological environment. Subsequently, multiple bioorthogonal click reactions have been developed and tested even in living animals. These subject reactions are currently used to explore cells, trace biological processes, etc.

For all these reasons, the potential of the Chemistry click is huge. This year's awardees have laid the foundation for a new functional form of Chemistry, in which bricks or building blocks are quickly and efficiently linked together to give countless combinations, in what can be thought of as a molecular Lego game. In this way, libraries of compounds are created that can accelerate the finding of new drugs. Although it is not possible to replicate natural molecules exactly through these reactions, molecules with similar functions can be developed. The development of these reactions click has also found applications, in addition to those already mentioned, in enzyme inhibitors, herbicides, photostabilizers, conjugation of biomacromolecules, diagnostic and sensitizing elements, corrosion retardants, tissue regeneration matrices, and many others.The Conversation