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On October 5, 2022, at about 17: 45 Beijing time, the 2022 Nobel Prize in Chemistry was awarded to American scholar Caroline R. Berthosi, Danish scholar Morten Merdahl, American scholar K. Barry Sharpless, in recognition of their contribution to the development of click chemistry and bioorthogonal chemistry.

Caroline R. Carolyn R. Bertozzi was born in the United States in 1966. He received his doctorate from the University of California, Berkeley in 1993. He is currently Anne T. And Professor Robert M. Bass.

Morten Merdahl (Morten Meldal) was born in Denmark in 1954. He received his doctorate from the Technical University of Denmark in 1986. He is currently a professor at the University of Copenhagen in Denmark.

k. Barry Sharpless (K. Barry Sharpless) was born in 1941 in Philadelphia, Pennsylvania. He received his doctorate from Stanford University in 1968. Professor W. M. Keck of Scripps Research Center in the United States. He shared the 2001 Nobel Prize in chemistry with two other scholars for "chiral catalytic oxidation". The award made him the second scientist to win the Nobel Prize in chemistry twice after Frederick Sanger (founder of protein sequencing and DNA sequencing).

Sometimes the simple answer is the best. Barry Sharpless and Morten Merdahl brought chemistry into the era of functionalism and laid the foundation for click chemistry (click chemistry). Berthosi shared the 2022 Nobel Prize in chemistry, which took click chemistry to a whole new dimension and began to use the tool to map cells. The biological orthogonal response developed by Berthod West has achieved a variety of applications, including promoting the development of more targeted cancer therapies.

Since the birth of modern chemistry in the 18th century, many chemists have taken nature as their imitation object. Life itself is the best proof that nature has the supreme ability to create chemical complexity. The amazing molecular structures found in plants, microbes and animals have prompted researchers to try to construct the same molecules through artificial synthesis. Imitating natural molecules is often an important part of drug development, because the inspiration for the development of many drugs comes from natural substances.

Its value has been proved by the chemical knowledge accumulated over the centuries. Using the complex tools developed, chemists can now create a variety of amazing molecules in the laboratory. A challenging problem, however, is that complex molecules have to go through many steps to build, each of which produces unwanted by-products-sometimes more and sometimes less. In order to obtain the desired compounds, these by-products must be removed before continuing with the subsequent reaction process. For those chemical structures which are difficult to synthesize, the loss of raw materials may be great, and the product is almost zero at the end of the reaction. Chemists can often achieve challenging goals, but the routes they take can be time-consuming and expensive. The 2022 Nobel Prize in Chemistry is about finding new and ideal chemistry that gives priority to simplicity and functionality.

Chemistry enters a new era of functionalism today, Barry Sharpless won his second Nobel Prize in chemistry. He was the first person to start rolling snowballs. Around the turn of the century, he created the concept of click chemistry for a functional chemistry. In click chemistry, molecular modules can be combined quickly and effectively. When Morten Meldahl and Barry Sharpless independently discovered the copper-catalyzed azide-alkyne cycloaddition reaction (copper catalysed azide-alkyne cycloaddition), the jewel in the crown of chemistry, the snowball became an avalanche.

Berthod West has developed a click response that can be applied to organisms. When applied in organisms, her biological orthogonal reaction can not interfere with the normal chemical process of cells, and is currently being used to draw the functional map of cells all over the world. Some researchers are now studying how to use these reactions to diagnose and treat cancer. Now let's look at the first of two clues leading to the 2022 Nobel Prize in chemistry.

The time when chemists needed a new ideal to unravel this clue began in 2001, when Barry Sharpless won the first Nobel Prize in chemistry. However, when he advocated a new minimalist approach to chemistry in a scientific journal, nothing had happened. He thinks it's time for chemists to stop imitating natural molecules-which often makes chemists encounter uncontrollable molecular synthesis, which poses an obstacle to the development of new drugs.

When a potential drug is found in nature, chemists can usually produce small amounts of the substance and use it in in vitro tests and clinical trials. Then, if industrial production is needed at a later stage, higher production efficiency needs to be achieved. Sharpless uses meropenem (meropenem), a powerful antibiotic, as an example. It took scientists around the world about six years to find a way to mass-produce this molecule.

"quarreling" molecules are expensive. According to Barry Sharpless, one of the stumbling blocks for chemists is the chemical bonds formed between carbon atoms, which are crucial to the chemical processes in life. In principle, all biomolecules have a framework for connecting carbon atoms. Life has evolved a way to create these substances, but it turns out to be notoriously difficult for chemists. The reason is that carbon atoms from different molecules usually lack the chemical driving force to form bonds, so they need to be activated manually. This activation usually leads to many unnecessary side reactions and costly loss of raw materials.

Instead of forcing carbon atoms to react with each other, Barry Sharpless encouraged his colleagues to start with smaller molecules that already have a complete carbon skeleton. These simple molecules can be connected by nitrogen or oxygen bridges that are easier to control. If chemists choose simple reactions-molecules combine together with a strong internal driving force-many side reactions will be avoided while raw material losses will be minimized.

Click chemistry-Barry Sharpless, a practical green chemistry with great potential, calls this robust method of constructing molecules "click chemistry". He believes that even if click chemistry does not provide exact copies of natural molecules, it is also possible to find molecules with the same function. Combining simple chemical blocks can create almost endless molecules, so he believes that click chemistry can produce new drugs with functions similar to natural medicines and can be produced on an industrial scale.

In his 2001 book, Barry Sharpless listed several criteria for chemical reactions that belong to click chemistry. One of them is that the reaction should take place in oxygen and in water, a cheap and environmentally friendly solvent.

He also cited several existing examples of chemical reactions, which he thought realized his new theory. However, no one knew at the time that it is now almost an excellent reaction for clicking chemical synonyms-copper-catalyzed azide-alkyne cycloaddition. This will be found in a laboratory in Denmark.

Change the click reaction of chemistry

When copper ions are added, the reaction between azides and alkynes becomes extremely efficient. This reaction is now widely used to connect molecules together in a simple way.

In many cases, decisive scientific advances occur at the most unexpected moments for researchers, as happened to Morten Meldahl. At the beginning of this century, he was developing ways to find potential drugs. He built a huge library of molecules that could contain hundreds of thousands of different substances and then screened them to see if any of them could block the disease.

In the process, he and his colleagues had a very routine reaction one day. You don't need to remember this, just know that their aim is to make alkynes (alkyne) react with acyl halides (acyl halide). If the chemist adds some copper ions and perhaps a small pinch of palladium as a catalyst, the reaction will usually go smoothly. But when Meldahl analyzed what was going on in the reaction container, he found something unexpected. It turns out that alkynes react with the wrong end of acyl halides. At the other end is a chemical group called azide (azide) (pictured above). Azides and alkynes form a cyclic structure, namely triazole (triazole).

People who know a little bit about this reaction may know that the chemical structure of triazoles is very useful, they are very stable and often appear in some drugs, dyes and agrochemicals. Because triazoles are ideal chemical structural units, researchers have previously tried to make them from alkynes and azides, but this can lead to unnecessary by-products. Morten Merdahl found that copper ions could control the reaction, yielding basically only one product, and the acyl halides that were supposed to be bonded to alkynes had more or less no reaction. In Merdahl's view, the reaction between azides and alkynes is clearly unusual.

He first presented his findings at a seminar in San Diego in June 2001. The following year, in 2002, he published an article in an academic journal saying that the reaction could be used to combine many different molecules.

Molecules "snapped" together quickly and effectively in the same year, Barry Sharpless (independent of Morten Merdahl) also published a paper on the reaction of azides and alkynes catalyzed by copper. This study shows that the reaction can work in water and is reliable. He described it as a "perfect" click response. Azide is like a pressed spring in which the force is released by copper ions. The process is stable, so Sharpless suggests that chemists use the reaction to connect different molecules. He thinks it has great potential. In retrospect, we can see that he was right. Now, if chemists want to connect two different molecules, they can relatively simply make one molecule have an azide group and introduce an alkynyl group into the other. Then, with the help of some copper ions, they can combine the two molecules.

Click response can create new materials. The simplicity of click response makes it popular in laboratory research and industrial production. Moreover, the click response also helps to produce new materials that need to meet specific needs. For example, if manufacturers add click-reactive azides to plastics or textiles, later material upgrades become easy, for example, this may enable the raw material to connect to substances that conduct electricity, obtain sunlight, antibacterial, UV radiation or other ideal properties, and to prevent softener leakage by fixing the softener in the plastic through a click reaction. In drug research, click chemistry can also be used to produce and optimize substances that may become drugs.

There are many examples of the power of click response. What Barry Sharpless did not expect, however, was that it would be used in the field of biology. Now, let's uncover the second clue to the 2022 Nobel Prize in chemistry.

The clue that Berthod West began to study elusive carbohydrates began in the 1990s, when biochemistry and molecular biology were undergoing explosive developments. Using new methods of molecular biology, researchers around the world are mapping genes and proteins in an attempt to understand how cells work. At that time, the academic circles were full of pioneering spirit, and new knowledge appeared in unknown fields every day.

However, one group of molecules received little attention: polysaccharides. Polysaccharides are oligosaccharides or polysaccharides polymerized by multiple monosaccharides, usually located on the surface of proteins and cells. They play an important role in many biological processes, such as when viruses infect cells or activate the immune system. Polysaccharides are indeed an interesting class of molecules, but the problem is that new tools in molecular biology cannot study them. As a result, anyone who wants to understand how polysaccharides work faces a huge challenge, and only a few researchers are ready to try to climb that mountain-Berthod West is one of them.

Berthod West has a brilliant idea. In the early 1990s, Caroline Berthod West began mapping polysaccharides that attract immune cells to lymph nodes. Due to the lack of effective tools, it will take her several years to understand how the glycan works. It made her wonder if there was a better way to make the process easier-she had an idea. At a seminar, she listened to a German scientist who explained how he succeeded in getting cells to produce an unnatural variant of sialic acid, a class of nine-carbon monosaccharides, one of the sugars that make up polysaccharides. So Berthod West began to wonder if she could use a similar method to get cells to produce sialic acid with some kind of chemical grip. The modified sialic acid can participate in the formation of different polysaccharides, and she can use chemical hands to locate them. For example, she can connect fluorescent molecules to the handle. The fluorescence can then show the position of the glycan in the cell.

This is the beginning of a long and focused development effort. Berthod West began searching the literature for possible chemical clutches and related chemical reactions. This is not an easy task because the grip cannot react with any other substance in the cell. It must be insensitive to all substances except the molecule she is going to connect to the grip. She coined a term to express this requirement: the reaction between the hand and the fluorescent molecule must be "biologically orthogonal" (bioorthogonal).

Simply put, in 1997, Berthod succeeded in proving that her idea worked. The new breakthrough came in 2000, when she found the best "chemical grip": azide. She cleverly modified a known chemical reaction, the Staudinger reaction (the Staudinger reaction), and used it to connect a fluorescent molecule to the azide she introduced into the glycan. Because azide does not affect cells, the compound can even be introduced into organisms. Based on this, she has made an important discovery in the field of biochemistry. Through these chemical processes, her modified Staudinger reaction can map the cells in a variety of ways, but Bertozi is still not satisfied. She has realized that the "chemical grip" she uses-azide-has more to do.

Inject new life into the old chemical reaction, when the click chemical reaction discovered by Morten Meldahl and Barry Sharpless spread among chemists, Caroline Berthod clearly realized that her grip, azide, as long as there is copper ion, can quickly click on an alkyne group. But the problem is that copper is toxic to living things. So she began again by digging up the literature and found that studies as early as 1961 showed that if there were alkynyl groups in a ring-shaped chemical structure, azides and alkynyl groups could still react in an almost explosive manner even without the help of copper. This reaction will release a lot of energy, so that the subsequent reaction can be carried out smoothly.

When she tested in the cell, the response was good. In 2004, she published the copper-free click reaction, named strain-promoted Cycloaddition of alkyne azides (strain-promoted alkyne-azide cycloaddition), and proved that it could be used to track polysaccharides (see chart above).

This milestone discovery is also the starting point for some of the greater discoveries. Caroline Berthosi has been improving her click response to make it work well in a cellular environment. At the same time, she and many other researchers began to use these reactions to explore how biomolecules in cells interact and to study the disease process.

One of Berthod's concerns is the polysaccharides on the surface of tumor cells. Because of her research, people began to realize that some polysaccharides on the tumor surface seem to protect the tumor from the body's immune system because they prevent immune cells from functioning. In order to suppress this protective mechanism of tumor, Bertolsi and his colleagues created a new class of biomedicine. They added polysaccharide-specific antibodies to some enzymes that target polysaccharides on the surface of tumor cells, and these enzymes break down polysaccharides. The drug is currently in clinical trials on patients with advanced cancer. Many researchers have also begun to develop click antibodies against a range of tumors. Once the antibody is attached to the tumor, it is injected with a second molecule that can be attached to the antibody by clicking. For example, a radioisotope can be added so that tumors can be tracked by PET scanners or lethal doses of radiation can be given to cancer cells.

Elegant, ingenious and novel, but most importantly useful-we don't know whether these new treatments will work-but one thing is clear: these studies have just revealed the great potential of click chemistry and bioorthogonal chemistry. In 2001, when Barry Sharpless gave his first Nobel Prize-winning chemistry speech in Stockholm, he talked about his childhood, which was deeply influenced by the simple values of Quakers, which also affected his ideals in life. "when I started doing research, elegance and ingenuity were the highest honor in chemistry, and now novelty is highly praised," he said. however, as a Quaker, what I value most is' usefulness'. " These four compliments are all necessary and can fairly praise the chemical reaction foundation laid by him, Caroline Berthosi and Morten Meldahl. In addition to elegance, delicacy, novelty and usefulness, their discoveries have also brought the greatest benefits to mankind.

Nobel Prize official website:

Https://www.nobelprize.org/

This article is from the official account of Wechat: global Science (ID:huanqiukexue), author: global Science

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