eat me?Want to eat me?Eat again ...

The old princes must love and hate. The deliciousness is really delicious, but its toxicity is really daunting. It is more than 1,000 times stronger than potassium cyanide, and it has a very fast effect. It can be settled to death within a few minutes to a few hours.

River in the ocean. Gallery copyright picture, not authorized reprint

For this kind of love and hate of He Yan, only the old ladies have the same old ladies, and chemists feel the same. What is love is that the poison of rivers has a specific inhibitory effect on nerve excitement, which can be used as an excellent neuropathic agent, which is great in the field of analgesics and anesthesia. Difficult! In 1972, when the poisonous molecule of the river was synthesized in the laboratory for the first time, it took 67 chemical reactions steps, but only reached 1% of the area. Such annoying steps and such a low output make this synthetic route almost no actual availability.

So, is chemist just right? of course not. They have been working hard to reduce the steps and increase the income. In July of this year, a study published in "Science" shortened the full synthesis steps of the poisonous molecules of the river to 22 steps, and the income rate reached 11%. This means that the synthesis of rumor toxins can be applied in industry, and new drug development based on rumor toxins will also be possible.

01. A cream of A, Honey

Why is Hehuan carrying such toxic? Although the toxins of the river are found in the river bodies, the real source is not the river. The toxins of the river are mainly from the microorganisms they eat (also from symbiotic and infected bacteria). In other words, many poisons of Hebu are also eaten in. The poison of the river also appears in other animals that also eat these microorganisms -such as starfish, conch, toad, etc. -on their bodies. However, these animals have a complete set of "anti -virus" mechanisms, so they are also poisonous from their mouths. They have nothing to do when they eat.

Hire toxic river crickets. Gallery copyright picture, not authorized reprint

If human beings are eaten by rivers, they are not so lucky. After this toxin enters the human body, it will quickly act on nerve peripherals and nerve centers, blocking sodium ion channels on the nerve cell membrane, hindering nerve conduction, and causing nerve paralysis to cause death.

The toxicity is so fierce that it looks mysterious, and people can't help curious: What do you look like with such a toxic element?

In the early days of the toxicity of the rumor, the molecular structure of the poisonous toxin toxin has always been a mystery. As early as 1909, Japanese scholars described the toxic components of river catfish eggs, and named it TetRodotoxin (TTX) based on the name of the Tetraodontidae of the river. In 1938, scientists extracted more purely toxic components from the river tadpole. For decades, people have only knew the structure of the river toxins. It was not until the 1950s that the monolithic crystals of the rivers were separated. After more than ten years, in 1964, at a international conference in Kyoto, the TSUDA KYOSUKE of the University of Tokyo, Japan, Hirata Yoshimasa and Hirata Yoshimasa and Nagoya University The three research teams of Woodward at Harvard University in the United States also reported the correct structure of rumin toxins, and the true face of rumin toxins finally surfaced.

The chemical formula of the poisonous molecule of the river is C11H17O8N3 and the molecular weight is 319.27, which is not a large molecule. At this time, chemists and biologists are more interested: this little thing is not big and can not bear! Is it worth studying!

The so -called "A frost, the honey of B", and the poison of the river, on the surface, is a kind of deadly poison, which can produce the magical effect of "poisoning with poison" in the right place.

Because the poison of the rumin can selectively bind to the sodium ion channel receptor on the surface of the nerve cell membrane, thereby blocking the potential of the action and inhibiting the conduction of nerve excitement. The "silence" and "excitement" of nerve cells play a role in analgesic, anesthesia, and sedation. Not only that, rumin toxins can also be used as a good drug drug. In 1998, a Canadian company successfully developed a new drug drug called Tetropin's drug use, which can be described as a great pioneering agency.

02. When the chemist's head is big, no functional group is innocent

We often look for some natural substances that can replace synthetic chemicals in the biological world, because they often have the exquisite structure and specific functions of the wonderful and natural talents, and we can use these characteristics to achieve clever goals. For example, biological enzymes can be used as a clever catalyst. It is precise, efficient, catalytic activity and selectivity that crushes a large wave of catalyst products in the laboratory. The regulatory mechanism is used to create the desired protein molecules, eliminating the troubles of making step -by -step production in the workshop. The ideas of these tasks are instead of "artificially synthetic things" with "natural things", and the synthesis of TTX is actually a bit "reverse" with this conventional idea -it is to use the "manual" method, which Re -engraving TTX "natural" neurotoxin. What's more, TTX's synthesis is difficult. TTX molecular structure diagram. Image source: wikipedia

TTX is a dazzling element. In fact, the carbon set of the molecule is not complicated. It is just a cycloin alkane plus C1 and C2 side chains, but it is in sharp contrast to it is a dense functional group on it.

First of all, the right side of the nitrogen atom in the above figure (the part with "n" in the figure) is called "胍 胍". The cymbal base is the toxic "culprit" of TTX, because it will bring positive electricity under the physiological pH value and interact with a negative electrical group with the receptor protein of the sodium ion channel;

Image source: wikipedia

Following the foundation of the base, you will see a cage -like structure (that is, a part of two six -dollar ring). This is a epoxy miscellaneous diamond, and it is also the core structure of TTX;

Image source: wikipedia

There are many hydroxyl groups inside and outside this "cage", which also adds a lot of complexity to the molecules. Among them, the hydroxyl groups near the cymbal base are not good. The combination of physical fitness can be said to be a toxic "accomplishment".

Image source: wikipedia

Calculated all, the entire molecule has 4 rings and 9 adjacent stereo centers.

When the chemist's head is big, no functional group is innocent. The density of the functional group, coupled with the high level of three -dimensional specificity, makes the synthesis of TTX very difficult. Therefore, the status of TTX in the field of synthetic chemistry is very high, and it has been regarded as a challenging research goal by chemists.

The first challenge was Kishi and Fukuyama of Nagoya University in Japan. They first reported the full synthesis of the heye toxins in 1972. This is an organic milestone achievement of organic synthesis, and no one surpasses it for more than 30 years. After more than 30 years of stagnation, from 2003, the full synthesis of TTX ushered in rapid development. Many research teams provided a variety of synthetic routes and will continue to optimize the synthesis strategy. However, the efficiency, income and selectivity of TTX have been unsatisfactory.

03. This simple and efficient new route

Until July this year, a joint team composed of Germany, the United States, and Japanese scientists published this new TTX full synthetic route in "Science". They started with a glucose derivative as the starting raw material and only needed 22 steps. You can get TTX -first win in simplicity. The other side of simpleness is practicality and economy, which means that the wonderful use of the poisonous poison we think, such as using it to make anesthesia, "magic medicine", etc., will be possible to become a reality.

Like many classic fully synthetic designs, this route also has amazing ingenuity and converting design. Of course, although the response steps have been "greatly" reduced to "only", it takes 22 steps. From the perspective of the gates, there are still some clouds in the clouds. Fortunately, the research team summarized these 22 steps into four big steps, and explained their synthetic strategies in accordance with the results of the result orientation and reverse deduction.

If we compare this TTX synthetic route to the four workshops on a factory in the factory, then the product of the last workshop should be TTX. The reaction of the fourth workshop is acelobeyolidazole (represented by 1). It performs oxidation reactions in the 4th workshop -of course, 1 as the reaction of the 4th workshop, and at the same time, it is also the same. The product of the 3rd workshop.

Picture source: science

Below to the 3rd workshop. If you want to get 1 at the end of the 3rd workshop, you can let the double ring isopopoline (represented by 2) enters the workshop as a reaction and reacts with the radical parent nuclear bonus.

Picture source: science

Next is how to get 2 in the 2nd workshop. In the 2nd workshop, nitro methane is a key role. We can understand that it stays in the 3rd workshop early. When only 3 came in, we can react with 1,3 bonus reactions in the molecule, and then get to get obtained 2. Therefore, the reactions and products of the 2nd workshop are 3 and 2, respectively.

Picture source: science

Although 3 seems to be the starting point of a complete synthetic route, the research team has discovered a more suitable starting material than 3 -a glucose derivative (represented by 4). If you complete this route with 4 as the starting raw material, all carbon and two stereo centers will be retained throughout the process. In this way, the workload of several follow -up workshops will be slightly smaller and the difficulty will be lower. Then, in the 1st workshop, what happened was from 4 to 3. Picture source: science

At this point, even if this new TTX fully synthetic route is over, it has set a record with the shortest and most efficient line in history with a 22 -step reaction and 11% revenue. So, what can it be used for?

First of all, its efficiency makes it have the value of application in industry, and can lay the foundation for the development of new drugs based on rumin toxins. In addition, there is actually a series of analogs in rumin toxins. This route can be changed slightly, which can also be used to synthesize other difficult to obtain rheotoxin toxins. Besides, there are still many things worth deeper in many fields such as biology, ecology, toxicology, neuroscience, etc.

Source: This article was produced by popular science China, produced by Gu Miaofei (Science Pictorial), and the Chinese Popular Science Expo Preparation

Selection and delivery unit: Computer Information Network Center of the Chinese Academy of Sciences

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