What Is Paclitaxel?

Taxol is also known as paclitaxel, taxol, taxol, and texol. It is the best natural anticancer drug that has been discovered. It has been widely used in the treatment of breast cancer, ovarian cancer and some head and neck cancer and lung cancer. As a diterpenoid alkaloid compound with anti-cancer activity, paclitaxel has been attracted by botanists and chemists due to its novel and complex chemical structure, extensive and significant biological activity, new and unique mechanism of action, and scarce natural resources. , Pharmacologists, and molecular biologists greatly favored it, making it an anti-cancer star and research focus that attracted worldwide attention in the second half of the 20th century. ^[1-2]

In 1963, American chemists MCWani and MonreE. Wall isolated for the first time a crude extract of paclitaxel from the bark and wood of Pacific Yew, which grows in large forests in the western United States. In screening experiments, Wani and Wall found that crude paclitaxel extract had high activity on mouse tumor cells cultured in vitro, and began to isolate this active ingredient. Due to the extremely low content of this active ingredient in plants, they were not identical until 1971.

Paclitaxel

Paclitaxel is a white crystalline powder, odorless, odorless, hardly soluble in water, and easily soluble

In 1979, Dr. Horwitz, a molecular pharmacologist at the Einstein College of Medicine in the United States, elucidated the unique antitumor mechanism of paclitaxel: paclitaxel can lose the dynamic balance of tubulin and tubulin dimers that make up microtubules, induce and promote Tubulin polymerization, microtubule assembly, and prevention of disaggregation, thereby stabilizing microtubules and inhibiting mitosis of cancer cells and preventing induction of apoptosis, thereby effectively preventing the proliferation of cancer cells and playing an anti-cancer role (Figure 4) [6 -10]. In fact, tubulin, which is closely related to cell mitosis, is common in almost all eukaryotic cells, and they can reversibly aggregate into microtubules. These microtubules are required for chromosome separation. After mitosis, these microtubules re-agglomerate into tubulin. The short-term disintegration of hammer-like microtubules can preferentially kill abnormally divided cells. Some important anticancer drugs such as colchicin, vinblastine, and vincristine, etc., prevent microtubulin by blocking tubulin. Anti-tumor effect due to re-polymerization. In contrast to anti-mitotic anti-tumor drugs, paclitaxel was the first drug discovered to interact with tubulin aggregates, that is, by tightly binding to microtubules, making them stable and functioning. At the same time, paclitaxel was found to act on a variety of entities. The tumor cells showed a good effect. This new discovery has attracted more biologists to use paclitaxel as a research tool in biomedicine, to explore unknown areas of cell activity and to discover new methods for new anticancer drugs. ^[2]

Paclitaxel Total Synthesis

Paclitaxel has attracted great interest from scientists due to its complex and novel chemical structure, unique biological mechanism of action, reliable anticancer activity, and serious lack of resources. According to statistics, more than 30 top laboratories around the world have invested in the total synthesis of paclitaxel, and the competition is fierce, becoming the focus of organic synthetic chemistry in the late 20th century. ^[2]

After more than 20 years of hard work, finally in 1994, two research groups, Florida State University chemist Holton and Scripps Institute chemist Nicolaou, reported the complete synthesis of paclitaxel at the same time. It is linear (first A ring, then AB ring, then ABC ring system) and convergent (first synthesize A and C rings respectively, and then assemble together to form ABC ring system) routes, representing different strategies for organic synthesis. The Holton research group is one of the earliest research groups engaged in the synthesis of paclitaxel. The Holton method uses cheap and readily available camphor as a starting material. Since the synthesis method of the paclitaxel side chain was developed by Ojima et al., It is also known as Holton. -Ojima method is characterized by few steps and high yield, and the total yield can reach 2.7%. Holton's total synthetic route for paclitaxel is characterized by meticulousness. The main reasons for its success are the intensive research on the molecular conformation and reactivity of paclitaxel after about 10 years, and the improvement and development of various chemical synthesis methods. Although Nicolaou's synthetic route has the advantage of being more concise than the former, its total yield is far lower than the former, only about 0.07%. After that, the Danishefsky team of Columbia University (1996), the Wender team of Stanford University (1997), the Kuwajima team of Japan (1998), and the Mukaiyama team (1999) also successively reported the complete synthesis of paclitaxel. ^[2]

The latest report from a group led by Professor Takahashi of Tokyo Institute of Technology in Japan in 2006 also completed the complete synthesis of paclitaxel. Although the seven total synthetic routes are different, they all have excellent synthetic strategies, which will raise natural organic synthetic chemistry to a new level. ^[2]

On the whole, the method of chemical total synthesis of the natural drug paclitaxel is too long and there are too many synthetic steps. Not only do expensive chemical reagents need to be used, but the reaction conditions are extremely difficult to control and the yield is low, which is not suitable for industrial production. However, many new and unique reactions have been discovered in the study of the total synthesis of paclitaxel, a large number of transition metal organic catalysts, the application of organosilicon reagents and the protection of groups during the reaction, the establishment and transformation of stereostructures, and unique strategies Ideas and reaction innovations play an important role in promoting and complementing organic synthetic chemistry and organic reaction theory. The research results of paclitaxel synthesis are still a monument in the history of organic chemical synthesis. At the same time, organic synthetic chemists are still actively engaged in the research of chemical total synthesis of paclitaxel, and make unremitting efforts to make the total synthesis of paclitaxel on the industrial road. ^[2]

Paclitaxel semi-synthesis

The total synthesis of paclitaxel cannot be commercialized due to the high cost of multiple steps, low yields, and harsh reaction conditions. The same problem is that the natural yew tree grows extremely slowly and is not easy to reproduce. A yew tree with a diameter of 22 cm and a height of 9 m is about 125 years old. Its bark is extremely thin and the thickness is about 0.3 to 0.6 cm. Such a tree can About 2 kg of bark is obtained, and paclitaxel must be extracted from freshly cut bark. About 30 g of dried bark can obtain about 100 g of paclitaxel. From cutting down trees, collecting yew bark to separating and extracting paclitaxel, it is time-consuming, labor-intensive and requires a lot of capital investment, and cutting down trees will lead to tree death and resource exhaustion. In a situation where paclitaxel has a complex structure that cannot be fully chemically synthesized, natural sources are very limited, and there is great social demand, looking for a higher amount of paclitaxel precursor compounds in yew and then chemically converting it to paclitaxel Very effective solution. ^[2]

It was found through research that although the biological activity of the taxol precursor compound baccatin III isolated from the taxus plant is lower than that of paclitaxel, it has the same mother-core structure as paclitaxel, and has a higher amount in the needles of the taxus, and can Paclitaxel was obtained through a four-step chemical reaction with a yield of up to 80%. This discovery has made significant progress in addressing new sources of paclitaxel, making mass production of paclitaxel possible. In 1993, a large amount of 10-deacetyl baccatin III (10-DAB) was found in the leaves of an ornamental plant Taxus chinensis, which was a renewable resource. Due to the relatively high amounts of baccatin III and 10-DAB in plants, semi-synthetic research efforts have focused on the study of these two substances. Dr. Denis of the University of Joseph Fourier in France first reported the research results of semi-synthetic paclitaxel from 10-DAB in 1988. Later, Professor Holton of the United States and Professor Potier of France applied for patents of semi-synthetic paclitaxel using baccatin III as raw materials. Potier believes that semi-synthesis is a promising way to solve the problem of paclitaxel supply. After obtaining the US FDA approval, Bristol-Myers Squibb Company used Holton's patent to produce paclitaxel, and decided to stop extracting paclitaxel from the bark at the end of 1994. At present, the semi-synthetic raw materials of paclitaxel are mainly derived from cultivated and cultivated yew, including a hybrid of Taxus chinensis and Taxus cuspidata Mandiana. ^[2]

Taxol Endophytic Fungi Synthesis

Stierle (1993) and Strobel (1993) first reported the isolation of a taxol-producing endophytic fungus Taxomyce sandreanae from Pacific yew trees, with a Taxol content of 24-50 ng / L, showing a possible production of Taxol Tempting new ways. Qiu Deyou et al. (1994) also reported that an endophytic fungus producing Taxol was isolated from the bark of Taxus yunnanensis Cheng et L.k. Fu (only TLC was made, and its content was not reported); Strobel (1996), Li & Strobel (1996) and others have reported that a variety of endophytic fungi producing Taxol have been isolated from yew trees and other plants, proving their biodiversity, and the yield range is 95 1081ng / L. The highest one can reach g level, and there is still a certain gap from the production level. We obtained 3 strains of Taxol-producing endophytic fungi in the same year through sampling and isolation. The Taxol content was 51.06 125.7 g / L after being cultured and analyzed. After several years of bioengineering and selection, the yield level of the strain was now Increased several times. ^[3]