For These Nobelists, Chemistry Clicks

Their development of click chemistry and bioorthogonal chemistry has contributed significantly to drug development and other fields

Earlier this month, the Royal Swedish Academy of Sciences awarded the Nobel Prize in Chemistry to Carolyn R. Bertozzi (Stanford University, CA, USA), Morten Meldal (University of Copenhagen, Denmark), and K. Barry Sharpless (Scripps Research, La Jolla, CA, USA) for the development of click chemistry and bioorthogonal chemistry.

The awardees specialise in the field of synthetic chemistry and bioorthogonal chemistry (a relatively new field that allows for performing chemical reactions in living systems, without disturbing their natural processes). (It is worth mentioning that this is the second Nobel Prize for K. Barry Sharpless, who won his first Nobel Prize in Chemistry in 2001 for his work on chirally catalysed oxidation reactions.)

Click chemistry: Like snapping molecules together

In general, click chemistry represents a group of chemical reactions that are selective, fast, simple to use and clean (easy to purify). Its main purpose is to connect two molecules, no matter how big or complex they are. Should their ends meet, they just ‘’click’’ to give a stable irreversible connection. Click chemistry reactions found applications (in addition to their use in synthetic chemistry) in a wide range of fields like analytical chemistry, chemical biology, drug development, bioconjugation, material and surface science. The beauty of it also lays in its simplicity; scientists and engineers from other fields (with no chemical training) can perform them easily as well.

Click chemistry is a term introduced by K. B. Shapless in 2001. His initial article “Click Chemistry: Diverse Chemical Function from a Few Good Reactions” describes a collection of chemical reactions that are very efficient and quick, without by-products or not interfered by those by-products. Since then, the development of this methodology has been evolving fast. The most popular and recognisable click chemistry reaction is 1,3-dipolar cycloaddition of azides to alkynes catalysed by copper. However, there are many others such as:

• Nucleophilic ring opening of aziridines, epoxides, cyclic sulfates, aziridinium ions, episulfonium ions, etc.
• Michael additions (addition of nucleophiles to electrophilic alkenes)
• Diels-Alder cycloadditions
• Formation of hydrazones or oxymes

The birth of biorthogonal chemistry

The wide range of chemical reactions considered click chemistry became very useful in many areas of science, but one particular aspect deserves highlighting. The huge success of copper catalysed azide-alkyne cycloaddition (CuAAC) initialised the interest in using this chemical transformation in biological systems. Unfortunately, the toxicity of copper ions to living organisms was a severe limitation of CuAAC in these systems. The solution for this drawback was found in using strained cyclic alkynes, which turned out efficient dipolarophiles for 1,3-dipolar cycloaddition. The reason why the copper ions are not necessary in the transformation is a massive bond angle deformation of alkyne that decreases the required activation energy and leads to efficient formation of the triazole product. This discovery was described by G. Wittig and A. Krebs in 1961, but Carolyn R. Bertozzi was the first who used this phenomenon to modify molecules in living systems in 2004. The novel work of Bertozzi and strain-promoted azide-alkyne cycloaddition (SPAAC) has since launched a new area of science – bioorthoogonal chemistry. It can be simply described as “…reactions of functional groups that are so selective for each other that they can be ligated in a richly functionalized biological milieu”. In addition to SPAAC, Bertozzi also used among others the Staudinger reaction discovered by H. Staudinger (Nobel Prize in Chemistry in 1953) and Jules Mayer in 1919. She demonstrated the utility of this reaction even in living animals.

Both click chemistry and its resulting subfield bioorthoogonal chemistry, have an undeniable impact on chemistry and other related areas of sciences. Their utility contributes to the development of enzyme inhibitors, pharmaceuticals (including anticancer agents and antimicrobials), photostabilizers, herbicides, diagnostic agents, tissue regeneration material, biomarkers, polymers and many more. The potential is still there to discover more in the future. The input and influence of Carolyn R. Bertozzi, Morten Meldal, and K. Barry Sharpless on science and scientific society is more than significant and it was recognized and reflected by this noble award.

Dr. Grzegorz Pikus received his PhD in organic chemistry at the Institute of Organic Chemistry, Polish Academy of Sciences in 2016. He spent 2 years at the University of Bristol, School of Chemistry in Bristol, UK, where he did his two post-doc positions, specialising in organic synthesis and supramolecular chemistry. Currently, he is a senior scientist at Charles River Laboratories, in the Small Molecule Drug Discovery Division in Harlow, UK.

Literature:

Wittig, G., Krebs. A., Chem. Ber. 1961, 94, 3260-3275.

Agard, N. J., Prescher, J. A., Bertozzi, C. R, J. Am. Chem. Soc. 2004, 126, 15046–15047.

Devaraj, N. K., Finn, M. G., Chem. Rev. 2021, 121, 6697-6698.

Kolb, H. C., Finn, M. G., Sharpless, K. B., Angew. Chem. Int. Ed. 2001, 40, 2004-2021.

Moses, J. E., Moorhouse, A. D., Chem. Soc. Rev. 2007, 36, 1249-1262.

Prescher, J. A., Dube, D. H., Bertozzi, C. R., Nature 2004 , 430, 873–877.

Ramström O., “Scientifc Background on the Nobel Prize in Chemistry 2022 CLICK CHEMISTRY AND BIOORTHOGONAL CHEMISTRY The Nobel Committee for Chemistry”, 2022.