It all basically started with Barry Sharpless having something to complain about in 2001. And not about the fact that he had just received his first Nobel Prize in Chemistry that year. But that, at least from his point of view, chemistry lacked suitable methods. It speaks for him that he didn't just complain. Instead, he laid the foundation for a new, extremely efficient type of chemical reactions, for the development and implementation of which he has now been awarded his second Nobel Prize in Chemistry together with the Dane Morten Meldal and the American Carolyn R. Bertozzi.
Sharpless complained that organic chemistry is based on the model of nature in the production of molecules. Their synthesis principle, which focuses on a so-called carbonyl group as a molecular building block, is simply unsuitable for quickly producing new molecules with desired properties. "With a few billion years and a planet, nature had plenty of time and resources left. We, as chemists on human time scales, do not have this, " he wrote together with his colleagues M. G. Finn and Hartmuth C. Kolb in the article in which the three coined the term click chemistry.
Sharpless had a very practical problem in view: the enormous effort that the pharmaceutical industry has to do to create medication with the desired properties based on natural substances. Living beings produce countless molecules with very specific properties. But they usually have a complex chemical structure with very long carbon chains; And to recreate them in the laboratory, you have to tedge them together with difficulty. "But these are not the only molecules that can have useful biological effects," the three researchers write.
A new chemistry toolbox
Sharpless had a completely different idea of how chemistry should work. Instead of a rumpel chamber from countless reactions, a well -sorted toolbox floated with a few, highly effective instruments. With these, a wide range of molecules should be made with little effort, which could then be tested for interesting properties. New medical active ingredients should no longer be based on molecules from nature, but on efficient chemistry that creates countless different molecular structures - and thus also countless new properties.
In order for this to work, the reactions have to meet several extraordinarily hard requirements. The two reaction partners must be so reactive that they "click" easily and permanently with each other, but at the same time they must not react with any other molecule or molecular part. In addition, the procedures should work with little effort both in the laboratory and on a large scale, Sharpless said. This means that the reaction should be under the best possible conditions, generate few by -products, and the end product must be easily separated.
Sharpless thus demanded little less than a reorientation of the previous chemistry. Away from carbonyl compounds, away from carbon-carbon bonds, away from artfully optimized reaction conditions and away from lousy yields and complex separation. Only perfect reactions come into the toolbox of click chemistry.
Sharpless soon had a reaction that actually makes "Click!" With the 1.3 dipolar cycloaddition, an azid- a chain made of three nitrogen atoms- reacts in a single step with a double or triple binding between two carbon atoms and forms a stable funnel ring. However, the reaction often runs slowly and results in a mixture of two different products - according to the two orientations in which the rod -shaped molecules can lie side by side.
The first perfect reaction
But the first of the perfect reactions were found in the same year. In Copenhagen, Morten Meldal and his colleague Christian W. Tornøe were interested in the five-seater-called five-triazole, which is created in the 1.3-dipolar cycloaddition of an azid with a triple binding between two carbon atoms, an alkin. This molecular part is also pharmaceutically interesting, and the two Danish researchers tried to couple it to an artificially produced peptide - without destroying the sensitive protein.
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The chemists encountered very similar requirements to those that Sharpless placed on his Click chemistry. The reaction conditions had to be mild, but the reaction nevertheless proceeded quickly and completely. The molecules involved must under no circumstances react with the different chemical groups of the peptide, and a mixture of different similar molecules must not come out.
In fact, Meldal and Tornøe came across an almost miraculous solution to the problem.
"When analyzing our results, we found that something strange was going on," says Meldal in an interview published on the Nobel Prices website.
If you add copper in its simply oxidized shape, all problems of the 1.3 dipolar cycloaddition seemed to be easy to evaporate.
The reaction suddenly took place very quickly, the chemicals involved reacted almost completely and – as no one had expected – only one of two possible versions of the product was ever created. "According to our understanding, the reactions we saw in the laboratory should not have taken place in this way," Meldal explains. Sharpless also soon came across a very similar procedure. Suddenly there was her, the perfect reaction.
Effective chemistry for biology
With this 1,3-dipolar cycloaddition of azides with alkynes, there suddenly was a fast, simple and reliable method to link chemical building blocks of all kinds together. It proved to be so practical for so many subfields of chemistry that it became one of the most important chemical coupling reactions almost overnight. In fact, they are still called the "click reaction" to this day, although there are now some more reactions for the toolbox targeted by Sharpless.
Since then, the click chemistry has attracted a lot more circles when Sharpless probably suspected in his vision of the chemical tool case. Last but not least, many of their properties also made the 1.3 dipolar cycloaddition interesting for biology and biochemistry. The reaction conditions are so mild that in principle you could use them in order to tie marking substances specifically to biomolecules and thus make structures visible in living cells. The only problem: copper is poisonous for cells.
To solve the problem, Carolyn R. Bertozzi went back to experiments that had been carried out in the middle of the 20th century with different versions of the 1,3-dipolar cycloaddition. It had turned out that the reaction took place much faster and more readily if the triple bond between the carbon atoms was not straight, but slightly bent – if it belonged to a ring.
The additional ring voltage makes the molecule significantly more reactive, so that the click reaction runs without copper. Bertozzi found that a triple binding in a eight -ring was reactive enough for her purposes. This creates two versions of the reaction product again, but the researcher didn't care - this technique is only about connecting. Cells that are fed with acid-containing sugar modules willingly install them in biomolecules. If you then connect the eight -ring with a marker substance, it shows the distribution of the biomolecule in the cell.
Bioorthogonal chemistry
However, the Click reaction was only an example of a much more extensive concept that Carolyn Bertozzi had previously considered.
Their goal was bio -orthogonal chemistry, in which chemical reactions run in the living cell without disturbing it or being disturbed by it.
Even before she made the click reaction used for biological systems, it had developed a similar system based on the so-called Staudinger coupling of acids and phosphorus-containing molecules.
The aim of the effort was to use the methods of classic chemical synthesis within individual cells and entire living beings in order to specifically mark certain molecules.
"What gave us the idea of bioorthogonal chemistry was our interest in making molecules visible on the cell surface," says Bertozzi. The principle is similar to click chemistry, but it is even more difficult to implement. This is well demonstrated by the example of 1,3-dipolar cycloaddition – copper is not a problem in the laboratory, but it is deadly in the cell. To do click chemistry in the cell, you still have to be a bit stricter.
The reward of the effort is a whole new window in the cell - one through which you can look at the most puzzling class of biomolecules. This is also confirmed by Bertozzi: "We were particularly concerned with the glycans," she says. These are branched sugar molecules that have many important functions in the body but are difficult to examine. With the help of bio -orthogonal chemistry, very fundamental discoveries are possible in this area. A team led by Carolyn Bertozzi in 2019 recognized that a large part of the RNA was wearing sugar molecules in cells. What this fabric class, known as glycorna, has functions is completely puzzling - without chemistry that even works in cells, we don't even know from you.
In organic chemistry, the precise, simple and reliable methods of click chemistry-of which there is now a whole bouquet-are even more important, from medication research to materials science. Of course, organic chemistry still uses carbonyl compounds, aggressive solvents and extreme reaction conditions, and the natural substances have not disappeared from medication research. But the toolbox that was imagined by Sharpless two decades ago has filled up since then - and the perfect reactions are only at the beginning of their development. "So far we have only scratched the surface of organic chemistry," says Meldal.
