Paclitaxel (PTX, or Pacific paclitaxel), a highly effective, low toxic, broad-spectrum natural anti-cancer drug[1], the molecular formula is Cforty-sevenHfifty-oneNOfourteen, which has been widely used in clinicalmammary cancer、oophoromaAnd sectionHead and neck cancerandlung cancerTreatment.Taxol, as an anti-cancer drugDiterpeneAlkaloid compounds, with their novel and complex chemical structure, extensive and significant biological activity, new and unique mechanism of action, and scarce natural resources, have been greatly favored by botanists, chemists, pharmacologists, and molecular biologists, making them a world-famous anti-cancer star and research focus in the second half of the 20th century.[1-2]Taxol is called chemotherapeutic drug, which can induce cell cycle arrest andmitosisDisaster to inhibit the proliferation of cancer cells.It is well known that paclitaxel can induce a variety of cell death in cancer[23]。In addition to the mitotic catastrophes that occur during induction of mitosis, paclitaxel has been shown to induce the expression of several pro apoptotic mediators, and it can also regulate the activity of anti apoptotic mediators.
The molecular formula of paclitaxel is Cforty-sevenHfifty-oneNOfourteen, relative molecular weight 853.91.Taxol is a white crystalline powder, odorless, tasteless, insoluble in water, easily soluble inmethanol、acetonitrile、chloroform、acetoneAnd other organic solvents, which are almost insoluble in waterpolyoxyethylenecastor oil(Cremophor EL) - anhydrous ethanol (50:50, v/v) solution as solvent.Taxol is easy to bind to the surface of glass or plastic in solution, resulting in a decrease in concentration.
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On August 21, 1962, Arthur S. Barclay, a botanist, came from the Pacific OceanYewThe tree bark was collected from more than 200 different plants.These samples were sent to the Wisconsin Alumni Research Foundation to prepare crude extracts for testing on oral epidermoid cancer cell cultures.On May 22, 1964, one of the tree samples was found to be cytotoxic in the cell activity test.Then, in late 1964 or early 1965, the fractionation and separation laboratory hosted by Monroe E. Wall in the North Carolina Triangle Research Park began to study the freshchinese yewThe active ingredient was isolated from the sample in September 1966, and their discovery was announced at the meeting of the American Chemical Society held in Miami Beach in April 1967.They named the pure active extract Taxol in June 1967.[4]
Calculate chemical data:
1. Reference value for drainage parameter calculation (XlogP): 2.5
2. Number of hydrogen bond donors: 4
3. Number of hydrogen bond receptors: 14
4. Number of rotatable chemical bonds: 14
5. Number of tautomers: 6
6. Topological molecule polar surface area (TPSA): 221
7. Number of heavy atoms: 62
8. Surface charge: 0
9. Complexity: 1790
10. Number of isotope atoms: 0
11. Determine the number of atomic structure centers: 11
12. Number of uncertain atomic structure centers: 0
13. Determine the number of chemical bond structure centers: 0
14. Number of uncertain chemical bond structure centers: 0
15. Number of covalent bond units: 1[3]
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Taxol is a kind of drug derived fromGymnospermschinese yewThe natural products purified from the bark ofSecondary metabolites, clinically proven to have good anti-tumor effect[15], especially for those with high incidence of canceroophoroma、uterine cancerandmammary cancerThere are special effects.Taxol is the most popular anti-cancer drug in the international market in recent years, and is considered to be one of the most effective anti-cancer drugs in the next 20 years.[1]
In recent years, the earth's population and cancer incidence rate have shown explosive growth, and the demand for paclitaxel has also increased significantly.Taxol for clinical and scientific research is mainly extracted directly from Taxus chinensis. Because the content of taxol in plants is quite low (only 0.069% of the bark of Taxus brevifolia, which is recognized as the highest content), only about 13.6 kg of bark can extract 1 g of taxol. It takes 3-12 taxus chinensis trees more than 100 years to treat an ovarian cancer patient,As a result, a large number of taxus chinensis were cut down, making this precious tree species endangered.In addition, the resource of Taxus itself is very poor, and the growth of Taxus plants is slow, which has caused great difficulties for the further development and utilization of taxol.[1]
Taxol biosynthesis pathway has been basically clarifiedDiterpenoidsThere are about 20 enzymatic steps from the precursor geranyl diphosphate to paclitaxel itself. This complex process can be divided into three parts: the source and formation of the paclitaxel core, the modification of the paclitaxel core skeleton, and the synthesis of the side chain of ß - phenylpropanoyl coenzyme A and the assembly of paclitaxel.Although chemical synthesis has been completed, it has no industrial significance because of the strict conditions required, low output and high funding.At present, the semi synthetic method of paclitaxel has been relatively mature, which is considered as an effective way to expand the source of paclitaxel in addition to artificial cultivation.Semi synthetic method can make greater use of plant resources, but it is not fundamentally different from the method of directly extracting paclitaxel, which requires a large number of taxus trees, and still cannot fundamentally solve the problem of lack of plant resources.Obviously, the extraction of taxol from Taxus chinensis plant tissue is greatly limited, and it is of great significance to find a new way to obtain taxol.[1]
structure
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Taxol, as an excellent anti-cancer drug, its molecular structure is extremely complex, containing 11 three-dimensional centers and a four ring skeleton closely constructed by 17 carbon atoms.This structural complexity has aroused the strong interest of many organic chemical synthesis research groups around the world.In 1989, Robert A. Holton of Florida State University used10 Deacetyl bacardine, a compound richly extracted from Taxus baccata, completed the semi synthesis of paclitaxel.On this basis, Holton successfully realized the first total synthesis of paclitaxel in 1994.Since then, five outstanding research groups, K · C · Nicolaou (1994), Danishefsky (1996), Wender (1997), Kuwajima (1998), Mukaiyama (1998), have respectively conceived ingenious synthesis strategies, injecting new vitality into this field.
Properties: white odorless and tasteless crystal or powder, insoluble in water, soluble in acetone, chloroform, ether and other organic solvents.
Albumin binding paclitaxel (nab paclitaxel, trade name: Abraxane) is a special form of paclitaxel. The main mechanism is to combine paclitaxel with nanoparticle albumin sodium by certain means.Many existing clinical toxicities of paclitaxel originate from the solvent Cremophor EL[10]。Therefore, albumin binding paclitaxel was used instead of Cremophor EL.In January 2005, the US Food and Drug Administration (FDA) approved the drug to be used for metastatic cancer without successful combination chemotherapy[16], or breast cancer that relapses within six months after adjuvant chemotherapy[11]。Since its approval, the drug has been used to treat locally advanced or metastatic non-small cell lung cancer[24], and application approval in the field of treatment of metastatic adenocarcinoma of the pancreas.[12]The following figure shows the structure of (−) - paclitaxel with anti-cancer activity:[9]
Structure of (−) - paclitaxel with anticancer activity [13][13]
Action mechanism
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In 1979, Dr. Horwitz, a molecular pharmacologist at Einstein Medical College, explained the unique anti-tumor mechanism of paclitaxel: paclitaxel canTubulinAnd tubulin, which forms microtubulesDimerLose dynamic balance, induce and promote tubulin polymerization, tubulin assembly, and prevent depolymerization, so as to stabilize microtubules and inhibit mitosis of cancer cells and trigger apoptosis, thereby effectively preventing proliferation of cancer cells and playing an anti-cancer role.
In fact, tubulin closely related to cell mitosis is almost ubiquitous in allEukaryotic cellThey can reversibly polymerize into microtubules, which are needed for chromosome separation.Microtubule is a component of cytoskeleton, which is distributed throughout the cytoplasm.It has the dynamic characteristics of polymerization and depolymerization, and plays an important role in maintaining cell morphology, cell division, signal transduction and material transport.Microtubules maintain cell structure and form cytoskeleton with microfilaments and intermediate fibers.They also constituteciliaandFlagellumIts internal structure provides a platform for intracellular transport and participates in a variety of cellular processes, including secretionVesicleThe movement of organelles and intracellular substances.In addition, they are also involved in cell division（mitosisandMeiosis）, including formationSpindle, and pulling apart eukaryotic chromosomes.After mitosis, these microtubules are again depolymerized into tubulin.The temporary disintegration of hammer like microtubules can preferentially kill cells with abnormal division, and some important anti-cancer drugs such asColchicine（colchicin）、Vinblastine（vinblastine）、vincristine(vincristine) and others play an anti-tumor role by preventing tubulin from re polymerization.In contrast to anti mitotic and anti-tumor drugs, paclitaxel is the first drug found that can interact with tubulin polymer, that is, by tightly combining with microtubules, make them stable and work. At the same time, it is found that paclitaxel shows good effects on a variety of solid tumor cells.This new discovery has attracted more biologists to use paclitaxel as a research tool in biomedicine, to explore the unknown field of cell activity and to discover new methods of anticancer drugs.[2]
synthetic method
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total synthesis
Taxol has aroused great interest of scientists due to its complex and novel chemical structure, unique biological mechanism, reliable anti-cancer activity and serious shortage of resources.According to statistics, more than 30 top laboratories around the world have been engaged in the research on the total synthesis of paclitaxel, and the competition is very fierce, which has become the focus of the field of organic synthetic chemistry in the late 20th century.[2]
After more than 20 years of efforts, in 1994, two research groups, Holton, a chemist at Florida State University in the United States, and Nicolaou, a chemist at Scripps Research Institute in the United States, reported the completion of the total synthesis of paclitaxel almost at the same time. They used linear (first ring A, then ring AB, then ring ABC)And convergent (first synthesize A and C rings respectively, and then assemble them together to form ABC ring system) routes represent different strategies for organic synthesis.
The Holton research group is one of the first research groups engaged in the synthesis of paclitaxel. The Holton method is cheap and easy to obtaincamphor(camphor) as the starting material, because the synthesis method of paclitaxel side chain was developed from Ojima, etc., it is also called Holton Ojima method, which is characterized by fewer steps, high yield, and the total yield can reach 2.7%.Holton's total synthesis route of paclitaxel is characterized by meticulous work. The main reason for its success is that it has experienced about 10 years of in-depth research on the molecular conformation and reactivity of paclitaxel, as well as the improvement and development of various chemical synthesis methods.
Although Nicolaou's synthetic route is simpler than the former, its overall yield is far lower than the former, only about 0.07%.Later, Danisefsky Group of Columbia University (1996), Wender Group of Stanford University (1997), Kuwajima Group of Japan (1998) and Mukaiyama Group (1999) also reported the completion of the total synthesis of paclitaxel.[2]
The latest report is that in 2006, a team led by Professor Takahashi of Tokyo University of Technology also completed the total synthesis of paclitaxel.Although the seven total synthesis routes are different, they all have excellent synthesis strategies, raising natural organic synthetic chemistry to a new level.[2]
In general, the chemical total synthesis method of natural drug paclitaxel has too long path and too many steps, which not only requires expensive chemical reagents, but also has extremely difficult reaction conditions and low yield, which is not suitable for industrial production.However, many new and unique reactions have been found in the study of the total synthesis of paclitaxeltransition metalThe application of organic catalysts and organosilicon reagents, the protection of groups in the reaction process, the establishment and transformation of stereo configurations, and the unique strategic thinking and reaction innovation have played an important role in promoting and supplementing organic synthetic chemistry and organic reaction theory.The research results of total synthesis of paclitaxel are still a monument in the history of organic chemical synthesis.At the same time, organic synthesis chemists are still actively engaged in the research work of chemical total synthesis of taxol, making unremitting efforts to make the total synthesis of taxol onto the road of industrialization.[2]
Semisynthesis
The total synthesis of paclitaxel cannot be commercialized because of its high cost due to many steps, low yield, harsh reaction conditions, etc.The same problem is that the natural red bean fir grows very slowly and is not easy to reproduce. A yew with a diameter of 22 cm and a height of 9 m is about 125 years old, and its bark is extremely thin, with a thickness of about 0.3~0.6 cm. Such a tree can get about 2 kg of bark, while paclitaxel must be extracted from the freshly cut bark, and about 100 g of paclitaxel can be obtained from 30 tons of dry bark.From felling trees, collecting yew bark to extracting paclitaxel, it is time-consuming, laborious and requires a large amount of capital investment. Moreover, felling trees will lead to tree death and resource depletion.Under the conditions of complex structure of paclitaxel and inability to realize chemical synthesis, limited natural sources and great social demand, it is a very effective solution to find a higher amount of paclitaxel precursor compounds in taxus and then convert them into paclitaxel by chemical methods.[2]
Through research, it was found that baccatin III, a precursor compound of paclitaxel isolated from Taxus chinensis, although its biological activity was lower than that of paclitaxel, it had the same maternal nuclear structure as paclitaxel, and its amount was higher in the needles of Taxus chinensis, and it could be obtained through four chemical reactions, with a yield of up to 80%.This discovery has made great progress in solving the new source of paclitaxel, making it possible to produce paclitaxel in large quantities.In 1993, more 10-deacetyl baccatin III (10-DAB) was found in the leaves of an ornamental plant, Taxus cuspidata, which is a renewable resource[14]。
Since the amount of baccatin III and 10-DAB in plants is relatively high, the research work of semi synthesis mainly focuses on the research of these two substances.In 1988, Dr. Denis of University Joseph Fourier of France first reported the research results of semi synthesis of paclitaxel from 10-DAB. Later, Professor Holton of the United States and Professor Potier of France applied for patents of semi synthesis of paclitaxel from baccatin III. Both Holton and Potier believed that semi synthesis was a promising way to solve the problem of paclitaxel supply.After obtaining the approval of the US FDA, Squibb used Holton's patent to produce paclitaxel, and decided to stop extracting paclitaxel from bark at the end of 1994.The semi synthetic raw materials of paclitaxel mainly come from artificially cultivated taxus, including a hybrid of Taxus mairei and Taxus mairei.[2]
Endophytic fungal synthesis
Stierle (1993) and Strobel (1993) reported for the first time that a taxol producingEndophytic fungiTaxomyce sandreanae，Its Taxol content is 24~50 ng/L, and people have shown an attractive new way to produce Taxol.Qiu Deyou et al. (1994) also reported that an endophytic fungus was isolated from the bark of Taxus yunnanensis to produce Taxol (only TLC was done, but its content was not reported).Strobel (1996), Li&Strobel (1996.Three strains of endophytic fungi capable of producing Taxol were obtained in the same year of sampling and isolation, and the content of Taxol reached 51.06~125.7 mg/L through cultural analysis. After several years of breeding by means of bioengineering, the production level of this strain increased several times.The researchers also used rare earth compounds to study the production of paclitaxel in plant cell culture, so as to improve its yield[17]。
Drug R&D
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In April 2023, Shanghai Yizhong said that paclitaxelmicelleIt is widely used in the treatment of various solid tumors, and the approved indication is the first-line treatment of non-small cell lung cancer;The phase III clinical trial of breast cancer with paclitaxel micelles has been approved by the Food and Drug Administration.[5]
In 2023, the team of Northwestern University School of Medicine reported the results of a Phase I human clinical trial. They used a new type of skull implant ultrasonic equipment to open theblood brain barrier[7]And repeatedly infiltrate chemotherapy drugs into large key areas of the human brain to enhance the therapeutic effect.The research results were published in the new issue of The Lancet Oncology.The 4-minute procedure to open the blood-brain barrier is carried out when the patient is awake, and the patient can go home in a few hours.The results showed that the treatment was safe and well tolerated. Opening the blood-brain barrier led to the increase of drug concentration in human brain by about 4-6 times.Scientists observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin.[6]
Albumin binding paclitaxel is a new kind of paclitaxel preparation, which has been used in the treatment of many solid tumors.This drug has a strong anti-tumor effect and is currently used in the treatment of ovarian cancer, breast cancer, pancreatic cancer and other diseases[18-21], but it has severe neurotoxicity[22], can cause peripheral neuropathy.Patients often express numbness of hands and feet, pain and burning sensation, which may lead to treatment interruption in serious cases. So far, there is no effective prevention and treatment method.
