Pharmacological action and extraction synthesis of artemisinin
Artemisinin, a sesquiterpene lactone drug extracted from the stems and leaves of Artemisia annua L., is an important antimalarial drug.
Chemical structure
Artemisinin has a molecular formula of C15H22O5, a molecular weight of 282.33, and a component content of C 63.81%, H 7.85%, and O 28.33%.
Physical properties
Artemisinin is a colorless needle-like crystal with bitter taste. It is soluble in acetone, ethyl acetate, chloroform, benzene and glacial acetic acid, soluble in ethanol and methanol, ether and petroleum ether, and almost insoluble in water. Melting point: 156-157 ° C.
Pharmacological action
Its effect on the ultrastructure of the Plasmodium falciparum red is mainly due to the change of the structure of the Plasmodium membrane system. The drug acts first on the food membrane, membrane, mitochondria, endoplasmic reticulum, and also has a certain chroma in the nucleus. Impact. The mode of action of artemisinin is mainly to interfere with the function of the membrane-mitochondria. It may be that artemisinic acid is starved, rapidly forms autophagic vacuoles, and is continuously discharged from the worm, causing the malaria parasite to lose a large amount of cytoplasm and die. In vitro cultured P. falciparum sputum-labeled isoleucine intake also showed that its initial mode of action may be to inhibit protozoal protein synthesis.
Combination therapy based on artemisinin has become the standard anti-malarial therapy recommended by the World Health Organization. According to WHO, artemisinin combination therapy is currently the most effective means of treating malaria, and it is also the best drug against malaria resistance. China is the founder and the largest producer of antimalarial drug artemisinin, fighting globally. The malaria process has played an important role.
Especially in Africa, the hardest hit area of ​​malaria, artemisinin has saved millions of lives. According to WHO statistics, since 2000, some 240 million people in sub-Saharan Africa have benefited from artemisinin combination therapy, and about 1.5 million people have avoided malaria-caused deaths.
Extraction process
The method for extracting artemisinin from Artemisia annua L. is based on the extraction principle, mainly including diethyl ether extraction and solvent gasoline extraction. The volatile oil is mainly extracted by steam distillation and separated by vacuum distillation. The process is: feeding-watering-distilling-cooling-oil-water separation-essential oil; non-volatile components are mainly extracted by organic solvent, column chromatography and recrystallization separation, basic process For: drying - crushing - soaking, extraction (repeated) - concentrated extract - crude - refined.
Artemisinin, although useful, is contaminated during the refining process. On October 5th, 2015, Nobel's physiology or medicine award was released, which made people know about Ningbo female pharmacist Tu Yu, and also knew artemisinin. The Ningbo Nuoda team brought by Tuyu discovered the artemisinin “environmental refining methodâ€, which opened the door for the green of medical chemistry.
Chemical synthesis
At present, artemisinin has high environmental and economic costs in its chemical extraction and synthesis process, and it not only needs to be refined under low temperature conditions, but also produces certain harmful substances.
Semi-synthetic route: From artemisinic acid as raw material, artemisinin is obtained after five steps of reaction, and the total yield is about 35-50%.
The first step: artemisinic acid is reacted with methanol under diazomethane/iodomethane/acid catalysis, and then selectively reduced by sodium borohydride in the presence of nickel chloride to obtain methyl dihydroartemisinate;
The second step: the methyl dihydroartemisinic acid is reduced to the artenimol with lithium aluminum hydride in a tetrahydrofuran or diethyl ether solution;
The third step: artemisinol is oxidized by ozone in methanol/dichloromethane/chloroform/carbon tetrachloride solution to obtain a peroxide, which is dried and then treated with p-toluenesulfonic acid in xylene to obtain a cyclic enolate. ;
The fourth step: the cyclic olefin ether is dissolved in a solvent, photooxidized in the presence of a photosensitizer rose red / methylene blue / hypocrellin to form a dioxetane intermediate, and then treated with an acid to obtain decarboxylated artemisinin;
The fifth step: decarboxylation of artemisinin is oxidized by an osmium tetroxide oxidation system or a chromic acid oxidant to obtain artemisinin.
Full synthetic route: Artemisinin can be fully synthesized by a variety of routes. For example, Schmil et al. reported in 1983 a complete synthesis route for the introduction of peroxy groups by photooxidation of a key compound enol ether at low temperature. The reaction was carried out using (-)-2-isomenthol as a raw material, retaining six yuan in the raw material. The ring, the three side chains on the ring are alkylated to form an intermediate, and finally the sesquiterpene lactone containing a peroxy bridge is synthesized. Xu Xingxiang reported the chemical synthesis pathway of artemisinin in 1986. The synthesis of artemisinin was carried out in fourteen steps using R-(+)-2 vanillin as raw material.
Biosynthesis
The biosynthesis of artemisinin and other sesquiterpenes is carried out in the cytoplasm. The pathway belongs to the plant isoprene metabolic pathway and can be divided into three major steps: formation of FPP from acetic acid, synthesis of sesquiterpenes, and relaconization to form blue. Artemisinin. : FPP→4,11-diene sesquiterpene→artemisinic acid→dihydroartemisinic acid→dioxyartemisinic acid peroxide→artemisinin. Artemisinin synthesis technology carried out in culture systems such as Artemisia annua L., Artemisia annua L. and A. aureus is highly likely to be used in industrial production.
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