Compared with the coldness of this year's Nobel Prize in Physiology or Medicine and Physics Award, this year's Nobel Prize in Chemistry is actually quite down-to-earth.
Some drugs you or people around you are using may come from their contributions.
022 Nobel Prize in Chemistry was jointly awarded to American chemist Caroline Bertosi, Danish chemist Morten Melda, American chemist Barry Sharples (the fifth scientist to win the Nobel Prize twice). 1. Sharples: Winning the Nobel Prize in Chemistry twice
In 2001, Barry Sharples won the Nobel Prize in Chemistry for "chiral catalytic oxidation reaction [1] [2] [3]", making great contributions to drug synthesis (and fragrances and other fields).
This year, his second award-winning "click chemistry" is also related to drug synthesis.
In 1998, Sharplas, who is already a leader in chiral catalysis, discovered a disadvantage of traditional biological drug synthesis.
Over the past 200 years, people have been able to find ingredients that can play the role of drugs in plants, animals, and microorganisms in nature, and then artificially construct the same molecules as possible to use them as drugs.
Although the industrialization of related drugs has made modern medicine a great success. However, as the required molecules become more complex, the difficulty of artificial construction is also increasing exponentially.
Although some chemists can indeed construct amazing molecules in the laboratory, it is almost impossible to achieve industrialization.
Organic catalysis is a complex process involving many steps.
Any step may produce more or less by-products. During the experiment, these by-products must be removed continuously at a cost.
is not only costly, it is also an extremely time-consuming process, and you may not even get the ideal product in the end.
In order to solve these problems, Sharpple proposed the concept of "click chemistry" with his extraordinary wisdom [4]. The determination of click chemistry in
was not achieved overnight. After three years of precipitation, it was not until 2001 that the Sharples team improved "click chemistry".
click chemistry is also called "link chemistry". In essence, it synthesizes complex macromolecules by linking various small molecules.
The reason why Sharplace had such an idea is actually inspired by nature.
Nature is like a chemist with magical abilities. It synthesizes rich and diverse complex compounds through a few monomer small components.
Nature creates molecules diversity far exceeds that of humans. She always uses some exquisite catalysts to complete the synthesis process using complex reactions. Compared with human technology, it is too rough and simple.
Some catalytic processes of nature are almost impossible for humans to complete.
Some drug development ended up going bankrupt, which was stuck in the huge trap set by nature.
Sharplace couldn't help but wonder, since the difficulty created by nature is insurmountable to humans, why don't we return it to nature? Let's skip this step?
Nature does not require the construction of C-C bonds from scratch, and does not require the recombination of starting materials and intermediates.
When adding large compounds, the construction of these C-C bonds can be very difficult. But directly using what nature has, finding a way to splice them together can also build complex compounds.
In fact, this method is like building blocks or LEGO. First assemble a fixed module (even clicking chemistry may not require assembling the module yourself, just use nature ready-made), and then think of a way to splice the modules together. The
Nobel platform provides the three chemists with vivid images [5] [6]:
Sharples gained inspiration from carbon-heteroatomic bonds and conceived a synthesis method based on carbon-heteroatomic bonds (C-X-C).
His ultimate goal is to develop a set of modules that can continuously expand. These modules are highly selective and can work stably and reliably in small and large applications.
"click chemistry" work is based on strict experimental standards:
- reaction must be modular, with a wide range of applications
- has very high yield
- only produces harmless by-products
- reaction has strong stereoselectivity
- reaction
- reaction
- reaction
- reaction
- reaction
- raw materials and reagents are easy to obtain The reaction of the product is stable under physiological conditions,
- is required to be atomic economy,
summarized a large number of carbon-heteroatoms, and in a paper [7] in 2002, the copper catalytic reaction between azide and alkyne ,
, chemistries summarized a large number of carbon-heteroatoms, and pointed out in a paper [7] in 2002 that the copper catalytic reaction between azide and alkyne is a reliable reaction that can be carried out in water. Chemists can use this reaction to easily connect different molecules.
He believes that the potential of this reaction is huge and can play a huge role in the field of medicine.
2. Meldar: How keen the intuition of screening available drugs
SharPress is, in the year he published this paper, another chemist made key discoveries in this regard.
He is Morten Merdal.
Meldal actually had no direct connection with "click chemistry" before the research on the reaction of azides and alkynes. Instead, he is a scientist who has a deep understanding of the research and development of "traditional" drugs.
In order to find potential drugs and related methods, he built a huge molecular library, including hundreds of thousands of different compounds.
He continued to screen over time, intending to screen out available drugs.
When using copper ion to catalyze the reaction of alkyne with acyl halide, an accident occurred. The wrong end (azide) of alkyne reacted with the acyl halide molecule, forming a ring structure - triazole.
triazole is a chemical component of various drugs, dyes, and key components of agricultural chemicals. In the past, in the process of research and development, the production of triazoles always produced a large number of by-products. However, this unexpected process, under the control of copper ions, no by-products were produced.
In 2002, Meldar published a related paper.
Sharplas and Meldar also officially converged in the field of "click chemistry" and promoted the copper-catalyzed azide-alkyne Cycloaddition reaction (Copper-Catalyzed Azide–Alkyne Cycloaddition), becoming the most widely used click chemistry reaction in the field of medicine and biology.
3. Bertozisi: Apply click chemistry to the human body
However, it is the American scientist Caroline Bertoci who further sublimates click chemistry.
Although the Nobel Prize three were evenly divided, it is not difficult to find that Caroline Bertosi ranks first, and she is also in the C position in the "click chemistry" composition. When
Nobel Prize in Chemistry, she also mentioned that she brought click chemistry to a new dimension.
She solved a very critical problem, applying "click chemistry" to the human body, and this application completely exceeded the unexpected by founder Charle Price.
This is the so-called bioorthogonal reaction , which is a chemical modification of living cells , and does not interfere with its own biochemical reaction in the organism.
Caroline Bertosi opened the door to bioorthogonal reaction, but in the beginning it had nothing to do with "click chemistry".
In the 1990s, with the explosive development of molecular biology , the mapping of genes and protein maps is in full swing around the world.
, however, is located on the surface of proteins and cells, and plays an important role in glycan , but there was no tool for analysis at that time.
At that time, Caroline Bertosi intended to draw a glycan map that could attract immune cells to lymph nodes , but it took a full four years to master the function of polysaccharide .
Later, inspired by a German scientist, she planned to add recognizable chemical handles to the glycans to identify their structure.
Since it is to react in the human body and does not affect the human body, this handle must be insensitive to everything and do not react with any other substances in the cell.
After reading a large amount of literature, Caroline Bertosi finally found the best chemical handle.
Coincidentally, this best chemical handle is exactly a kind of azide, click the soul of chemistry. By combining fluorescent substances with cellular glycans by azides, the structure of glycans can be analyzed well.
Although Bertosi's research results are already epoch-making, she is still not satisfied because the reaction speed of the azide is not ideal.
Just then she noticed the click chemistry between Barry Sharples and Morten Meldal.
She found that copper ions can speed up the binding of fluorescent substances, but copper ions are very toxic to organisms. She must think of a way that can speed up the reaction without copper ions.
After reading a large amount of literature, Bertosi was surprised to find that as early as 1961, some studies found that when alkynes were forced to form a ring-shaped chemical structure, they would react with the azide in an explosive manner.
In 2004, she formally established the copper-free click chemical reaction (also known as strain-promoting azide-alkyne cycloaddition), which became a major milestone in click chemistry.
Bertoci not only drew the corresponding cell glycan map, but also applied it to the tumor field.
will form glycans on the surface of the tumor, which can protect the tumor from the immune system. Bertosi's team used bioorthogonal reactions to invent a drug specifically targeting tumor glycans. After this drug enters the human body, it will target the destruction of tumor glycans, thereby activating the body's immune protection.
The drug is currently undergoing clinical trials in patients with advanced cancer.
is not difficult to find that although the translations of "click chemistry" and "bioorthogonal chemistry" seem obscure and difficult to understand, there are actually very simple principles behind it. One is a splicing like a snap, and the other is a splicing that can be used directly in the human body.
"Click chemistry" and "bioorthogonal chemistry" are still very young fields, and may have a more profound impact on the future of mankind.
Reference
- ^https://www.nobelprize.org/prizes/chemistry/2001/press-release/
- ^Pfenninger, A. Asymmetric Epoxidation of Allylic Alcohols: The Sharpless Epoxidation[J]. Synthesis, 1986, 1986(02):89-116.
- ^Rao A S . Addition Reactions with Formation of Carbon–Oxygen Bonds: (i) General Methods of Epoxidation - ScienceDirect[J]. Comprehensive Organic Synthesis, 1991, 7:357-387.
- ^Kolb HC, Finn MG, Sharpless KB. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew Chem Int Ed Engl. 2001 Jun 1;40(11):2004-2021.
- ^https://www.nobelprize.org/uploads/2022/10/popular-chemistryprize2022.pdf
- ^https://www.nobelprize.org/uploads/2022/10/advanced-chemistryprize2022.pdf
- ^Demko ZP, Sharpless KB. A click chemistry approach to tetrazoles by Huisgen 1,3-dipolar cyclloaddition: synthesis of 5-acyltetrazoles from azides and acyl cyanides. Angew Chem Int Ed Engl. 2002 Jun 17;41(12):2113-6. PMID: 19746613.
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