Heavy: The magical chiral molecular sieve is finally here! The pharmaceutical industry may be victorious
Release date: 2017-05-09 In the 1960s, there was a strange phenomenon. In just a few years, more than 10,000 newborn babies worldwide suffered from a disease called seal limbs (like seals). You know, the seal limb is an extremely rare disease. How can it suddenly erupt? Scientists quickly launched a wide range of investigations and found that the chief culprit was a drug called thalidomide (also known as reaction stop). The reaction stop is a sedative introduced in the 1950s. It is very effective for pregnant women who have very early pregnancy reactions such as nausea and vomiting. However, the manufacturer Grünenthal GmbH, which stopped the reaction, did not expect that the reaction they produced was a drug and not a drug. Of course, we are not discussing philosophical issues today. What is the meaning of this sentence? Seal limb children Let's look at an example first. Most people have two hands, although they all call hands, but most people can clearly feel that the left and right hands are different. We can say that they look exactly the same, but they are completely different. Because they are mirror-symmetrical, they cannot overlap. For the left-hander, the left hand is good, the normal person is the right hand. Some things in life are left-handed, some things are right-handed, and vice versa, even messing things up. Scientists call this phenomenon "chirality." Speaking of this, you may have realized that the reaction stop is definitely a "chiral" phenomenon. Indeed, scientists later discovered that there are two "chiral" symmetrical conformations in the process of production. They do not call left reaction stop and right reaction stop, but R-reaction stop and S-reaction stop. Type R has a significant pharmacological effect of inhibiting the pregnancy response, while type S produces severe to abnormal side effects (4). Reaction stop This incident has caused great concern about drugs with "chiral" nature, and the FDA has made clear regulations for the clinical study of such drugs. In the pharmaceutical sector, 56% of the drugs are "chiral". What should I do? Unless you can prove that there are no side effects when mixing together, you have to kick off the other one as much as possible from the mixed drug. This is like picking out left hooves from countless pig's trotters. The pig's trotters are so big that they can be sorted out quickly on the Foxconn-level assembly line, but the chemical drugs are so small and so many. In fact, the separation of chiral compounds has been a hot topic in the field of chemistry. Although there are many methods for the separation of chiral compounds, they are time consuming, laborious, and expensive, which greatly limits the application of chiral compounds. Time is coming to 2017. In April of this year, at the California Institute of Technology, a group of international researchers led by Professor Mark E. Davis successfully developed the world's first chiral molecular sieve (1). This discovery undoubtedly opens up new research areas in the fields of chemistry and biology and will be widely used in pharmaceutical companies and other chemical companies. This discovery will greatly increase the market share of chiral compounds. Professor Davis The screen that Dr. Davis invented was so powerful that we are not showing it for the time being. Let me talk about why the same chemical composition can form two structures with different spaces. When a carbon atom forms an organic molecule, it is sometimes connected to four groups, and a carbon atom connects four groups to form a spatial three-dimensional structure. When these four groups are not at the same time, they form two molecular structures, which are symmetric about the mirror surface but cannot overlap. That is to say, these two molecular structures represent two different substances. Because these two substances can't make them overlap in any three-dimensional space, just like the left and right hands of people, people call these two substances "chiral" molecules, which are almost identical in physical properties. But it is quite far from chemical (2). Chiral molecule In fact, "chirality" is not far from us. The documented study of "chiral" compounds dates back to 1848. Prior to 1848, the existence of optical isomers and racemates (equal mixtures of two heterogeneous "chiral" molecules) was unknown, and it was not known how to opticalize two optics in the racemate. The isomers are separated. However, in 1848, the French chemist, biologist Louis Pasteur, discovered a compound called sodium ammonium tartrate during the brewing process, and produced two crystals of completely different crystal forms during crystallization at 28 ° C. He measured the optical rotation of the two crystal forms, and as a result, one crystal produced polarized light to the right, and one crystal produced polarized light to the left, and the two crystals were mixed in equal amounts to lose optical activity. Therefore, Pasteur is the first person to discover "chirality" (3). Pasteur and tartaric acid crystals However, it took people nearly a century to discover that "chirality" played a very important role in animals, plants, agriculture, chemicals and pharmacy. All proteins, enzymes, and alkaloids and hormones that are part of nucleic acids are "chiral" compounds. Compared to synthetic chiral products, all natural "chiral" substances are single optical isomers. For example, all natural amino acids are left-handed, and all natural sugars have right. Optically active, this has a high degree of stereoselective correlation with all enzymes, receptors, etc. in animals and plants (4). Although these isomers have the same chemical composition, the two optical isomers of most of the racemic drugs have significant differences in pharmacological action, toxicity, and metabolism. The use of a single isomer drug is often better than a racemic mixture, with less toxicity and better patient compliance. For example, the commonly used cardiovascular drug beta-adrenergic receptor blocker propranolol, the activity of the levorotatory isomer is 100 times higher than that of the dextro-isomer, and the commonly used drug for treating Parkinson's disease is levodopa. Its dextro-isomers cause unacceptable side effects (5). Therefore, the resolution of the racemic drug or the direct synthesis of a single enantiomer is particularly important for the pharmaceutical industry, the chemical industry, and the like. The most important method currently used for chiral drug resolution is high performance liquid chromatography (HPLC). The synthesis of a single enantiomer is mainly achieved by asymmetric synthesis. The 2001 Nobel Prize in Chemistry awarded three scientists dedicated to chiral catalytic hydrogenation, William Knowles, who discovered that transition metals can be used to hydrogenate chiral molecules to obtain the final product with the desired mirror image. . Yeyi Liangzhi further perfected the process for the chiral catalyst for hydrogenation. Barry Sharpes has developed a chiral catalyst for the oxidation reaction. Three Nobel Prize winners in Chemistry The discovery of "chiral" molecular sieves is expected to significantly reduce the cost of production of single enantiomers, making them dominant in the pharmaceutical market. Through computer-aided design, researchers use organic organic directing agents to react with inorganic components to produce crystalline organic-inorganic composites. After removal of the organic structure directing agent, it is required to produce various applications (catalysis, separation, ion exchange and adsorption, etc.), high temperature resistant, hydrolysis resistant micropores (6) having a diameter of less than 2 nm associated with the spatial structure of the organic structure directing agent. . These small holes are the key parts of the "chiral" molecular sieve. In fact, molecular sieves are equivalent to a filter. Within the millions of small pores inside the molecular sieve, only compounds of similar size to the organic structure directing agent can enter the pores and be retained, while other compounds are eluted to achieve the separation effect. Therefore, by changing the structure of the organic structure directing agent and adding different catalysts to the inorganic material, various molecular sieves can be produced, providing shape selection properties, and in combination with catalytic active sites, can produce numerous high selectivity chemistry reaction. Thus, one can produce the desired levorotatory enantiomer, the right-handed enantiomer or the racemate (6) at low cost. All in all, "chiral" molecular sieves can be used not only for the synthesis of single enantiomers, but also for the resolution of the racemates, but also for repeated use, which can minimize the pharmaceutical industry, the chemical industry, etc. cost. The future pharmaceutical market must belong to a single enantiomer. Reference materials: 1.http:// 2. Cahn R S, Ingold C, Prelog V. Specification of molecular chirality [J]. Angewandte Chemie International Edition in English, 1966, 5(4): 385-415. 3.Flack H D. Louis Pasteur's discovery of molecular chirality and spontaneous resolution in 1848, together with a complete review of his crystallographic and chemical work [J]. Acta Crystallographica Section A: Foundations of Crystallography, 2009, 65(5): 371 -389. 4. Nguyen L A, He H, Pham-Huy C. Chiral drugs: an overview[J]. Int J Biomed Sci, 2006, 2(2): 85-100. 5. Noyori R. Asymmetric catalysis: science and opportunities (Nobel Lecture) [J]. Angewandte Chemie International Edition, 2002, 41(12): 2008-2022. 6.http://#sec-6 Source: Singularity Network The automatic biochemical analyzer is an instrument that measures a specific chemical composition in body fluids according to the principle of photoelectric colorimetry. Due to its fast measurement speed, high accuracy and small consumption of reagents, it has been widely used in hospitals, epidemic prevention stations and family planning service stations at all levels. The combined use can greatly improve the efficiency and benefits of routine biochemical testing. Bio Chemistry Analyzer, Clinical Chemistry Analyzer, Blood Chemistry Analyzer,Urine Chemistry Analyzer Jilin Sinoscience Technology Co. LTD , https://www.contoryinstruments.com
principle
The automatic analyzer is to automatically run all or part of the steps of sampling, mixing, warm bath (37°C) detection, result calculation, judgment, display and printing results and cleaning in the original manual operation process. Today, biochemical tests are basically automated analysis, and there are fully automatic biochemical analysis systems designed for large or very large clinical laboratories and commercial laboratories, which can be arbitrarily configured according to the laboratory's testing volume.
Whether it is the fastest-running (9600Test/h) modular fully automatic biochemical analyzer today, or the original manual-operated photoelectric colorimeter for colorimetry, the principle is the use of absorption spectroscopy in spectroscopic technology. It is the most basic core of the biochemical instrument.
Optical system: is a key part of ACA. Older ACA systems used halogen tungsten lamps, lenses, color filters, and photocell assemblies. The optical part of the new ACA system has been greatly improved. ACA's beam splitting system can be divided into front splitting and rear splitting due to different light positions. The advanced optical components use a set of lenses between the light source and the cuvette to convert the original light source. The light projected by the lamp passes through the cuvette to bring the beam to the speed of light (unlike traditional wedge beams), so that the spot beam can pass through even the smallest cuvette. Compared with traditional methods, it can save reagent consumption by 40-60%. After the spot beam passes through the cuvette, the spot beam is restored to the original beam through this group of restoration lenses (wide difference correction system), and is divided into several fixed wavelengths (about 10 or more wavelengths) by the grating. The optical/digital signal direct conversion technology is used to directly convert the optical signal in the optical path into a digital signal. It completely eliminates the interference of electromagnetic waves to the signal and the attenuation in the process of signal transmission. At the same time, the optical fiber is used in the signal transmission process, so that the signal can achieve no attenuation, and the test accuracy is improved by nearly 100 times. The closed combination of the optical path system makes the optical path without any maintenance, and the light splitting is accurate and the service life is long.
Constant temperature system: Since the temperature of the biochemical reaction has a great influence on the reaction results, the sensitivity and accuracy of the constant temperature system directly affect the measurement results. The early biochemical instruments used the method of air bath, and later developed into a dry bath with constant temperature liquid circulation which combines the advantages of dry air bath and water bath. The principle is to design a constant temperature tank around the cuvette, and add a stable constant temperature liquid that is odorless, non-polluting, non-evaporating and non-deteriorating in the tank. The constant temperature liquid has a large capacity, good thermal stability and uniformity. The cuvette does not directly contact the constant temperature liquid, which overcomes the characteristics of the water bath type constant temperature being susceptible to pollution and the uneven and unstable air bath.
Sample reaction stirring technology and probe technology: The traditional reaction stirring technology adopts magnetic bead type and vortex stirring type. The current popular stirring technology is a stirring unit composed of multiple groups of stirring rods that imitate the manual cleaning process. When the first group of stirring rods is stirring the sample/reagent or mixed solution, the second group of stirring rods performs high-speed and high-efficiency cleaning at the same time. The set of stirring bars also undergoes a warm water washing and air drying process at the same time. In the design of a single stirring rod, a new type of spiral high-speed rotating stirring is adopted, and the rotation direction is opposite to the spiral direction, thereby increasing the stirring force, the stirred liquid does not foam, and reducing the scattering of light by microbubbles. Reagent and sample probes are based on the principle of early capacitive sensing, but slightly improved to increase the alarm of blood clots and protein clots, and re-test results according to the alarm level, reducing sample aspiration errors and improving the reliability of test results. . Large-scale biochemical instruments can detect more than 1,000 tests per hour, so automatic retesting is very important. Subjective evaluation of test results and manual retesting can no longer meet clinical needs.
Other aspects: barcode recognition of reagents and samples and computer login. Due to the lack of barcode recognition function of early biochemical instruments, there are more opportunities for errors. In recent years, both imported and domestic chemical instruments have adopted barcode detection. The use of this technology in biochemical instruments has provided technical support for the development of high-speed ACA, and also made the instrument quite supportive. The software development is simple and easy, therefore, barcode detection is the basis for the intelligence of the instrument. Open reagents, as an important factor for hospitals to choose models, whether the instrument supports open reagents is very important. After the reagents are opened, hospitals and scientific research units can choose their own reagent suppliers, and have a greater degree of freedom in measuring the price, the reliability of the test results, and the validity period of the reagents. Ion Selective Electrode Analysis Accessory (ISE), human serum and urine electrolyte indicators are very important, and hospitals can save money by adding ISE to the ACA system.