There have been different opinions on the range and systematic position of Taxodiaceae. Shi Ni (1920) classified the genus Cymbidium into Taxaceae according to the distribution of suture bundles of seeds and their testa.
R pilger (1926) merged the genera of Cephalotaxus into Cephalotaxus. Dou Jiu (193 1) separated Cephalotaxus from Cephalotaxus as a new subfamily of Cephalotaxus.
In the same year, Dou Jiu and Yamamoto established the Taxodiaceae. Takhtadzhuyan (1956) thinks that Taxus chinensis is unique, and its external morphology and wood structure are quite similar to that of Podocarpus, so it is classified as Podocarpus.
However, most scholars believe that the five genera of Taxaceae have many similarities and are natural taxa. Florin (1948) upgraded Taxodiaceae to Taxodiaceae according to the fact that the female cone has a single terminal ovule.
While H. Melchior et al. (1954) upgraded Taxodium to Taxodium. However, this view has not been supported by taxonomic, morphological, anatomical, embryonic, cellular, biochemical and phytochemists. Almost all of them have proved from their own research that Taxodiaceae belongs to Taxodiaceae (or order), and its genetic relationship is closely related to Cephalotaxus and Podocarpaceae.
The ovule of Taxodiaceae is not true terminal, but false terminal. Single ovule is the last stage of female cone evolution of Taxodiaceae. .
2. The historical origin of Taxodiaceae. Taxodiaceae originated earlier. According to the existing fossil records, Taxus chinensis and Cephalotaxus fortunei began to appear in the Middle Jurassic, Taxodium ascendens began to appear in the Late Cretaceous and distributed in Europe, Asia and North America in the Neogene. After the Quaternary Glacier, Cephalotaxus and Taxodium became extinct in Europe and Europe and North America, forming a modern distribution pattern.
There have been different opinions on the range and systematic position of Taxodiaceae. Shi Ni (1920) classified the genus Cymbidium into Taxaceae according to the distribution of suture bundles of seeds and their testa. R pilger (1926) merged the genera of Cephalotaxus into Cephalotaxus. Dou Jiu (193 1) separated Cephalotaxus from Cephalotaxus as a new subfamily of Cephalotaxus. In the same year, Dou Jiu and Yamamoto established the Taxodiaceae. Takhtadzhuyan (1956) thinks that Taxus chinensis is unique, and its external morphology and wood structure are quite similar to that of Podocarpus, so it is classified as Podocarpus. However, most scholars believe that the five genera of Taxaceae have many similarities and are natural taxa.
Florin (1948) upgraded Taxodiaceae to Taxodiaceae according to the fact that the female cone has a single terminal ovule. While H. Melchior et al. (1954) upgraded Taxodium to Taxodium. However, this view has not been supported by taxonomic, morphological, anatomical, embryonic, cellular, biochemical and phytochemists. Almost all of them have proved from their own research that Taxodiaceae belongs to Taxodiaceae (or order), and its genetic relationship is closely related to Cephalotaxus and Podocarpaceae. The ovule of Taxodiaceae is not true terminal, but false terminal. Single ovule is the last stage of female cone evolution of Taxodiaceae.
3. The source and discovery process of paclitaxel were discovered by Dr. Wall and Dr. Varney of the Triangle Institute in North Carolina, USA in 1967.
Later, they isolated this compound from Taxus Pacific and found that it has a wide range of anti-malignant effects. Because paclitaxel can be decomposed into two crystallizable parts by the alcoholysis of Zemplen, at 1970, two scientists from Triangle Institute confirmed its structure by X-ray diffraction analysis, and published this research result at 197 1.
Taxol molecule is an extremely complex tetracyclic diterpene compound: a taxane ring plus an alkoxy ring consists of four elements, and C-2 and C- 13 have phenoxy and ester side chains respectively. Although paclitaxel has shown strong cytotoxicity to malignant tumors in tissue culture and several malignant tumor cell lines, it has not attracted enough attention in the past decade after its discovery. There are two main reasons for this: first, its resources are extremely limited; Secondly, its water solubility is poor.
Water solubility is very important for anticancer drugs, but paclitaxel is almost insoluble in water (its maximum solubility is about 20mg/L). At the same time, Wall and Vanni continue to eagerly study the broad-spectrum anticancer activity of paclitaxel they found.
1979 SusanHorwitz of Albert Einstein Medical College reported the unique mechanism of action of paclitaxel, which made it enter the embryonic stage of becoming a new class of tumor chemotherapy drugs. In fact, tubulin, which is closely related to cell mitosis, exists almost universally in all eukaryotic cells.
Microtubule proteins themselves are diverse. In mammals, there are at least six kinds of α -tubulin and the same amount of β -tubulin, each of which is encoded by different genes. These different types of tubulin are very similar, and they can be reversibly polymerized into microtubules.
Chromosome separation needs the help of these microtubules. After mitosis, these microtubules depolymerize into tubulin again.
The disintegration of hammer microtubules in a short time can kill abnormal dividing cells first. Some important anticancer drugs, such as colchicine, vinblastine and vincristine, play a role by preventing tubulin from re-polymerizing. Contrary to these antimitotic drugs, paclitaxel is the first drug known to interact with tubulin polymers, which can closely bind microtubules and stabilize them.
In addition, tubulin promoted by paclitaxel can be polymerized without GTP (GTP is usually needed to polymerize tubulin into microtubules). Under the conditions favorable for tubulin depolymerization, such as low temperature, calcium ion and dialysis, the tubulin polymer formed by paclitaxel is still stable.
Compared with α, β-tubulin dimer, according to chemical calculation, paclitaxel only binds to one of α, β-tubulin reversibly and specifically. However, studies have shown that when the concentration is nano-mole, paclitaxel shows similar effects to colchicine and Catharanthus roseus alkaloids at the same concentration, that is, it plays a role by preventing tubulin from polymerizing into microtubules.
In addition, paclitaxel can also induce the formation of specific tubulin bundles in cells. The success of the above research rekindled people's enthusiasm for further research and development of paclitaxel.
At the same time, the American National Cancer Institute has obtained a large number of clinical research data. Johns Hopkins University School of Medicine reported the amazing curative effect of paclitaxel on advanced ovarian cancer, which was included in the domestic medical yearbook 1989.
In the same year, Squibb was appointed as a partner by the American National Cancer Institute to develop and industrialize paclitaxel. 199 1 year, Dr. Broder, director of the American National Cancer Institute, asserted that paclitaxel would become the most important anticancer drug in the world in the future 15 years.
199265438+In February, paclitaxel was approved by the US Food and Drug Administration and became a therapeutic drug for advanced ovarian cancer. It was subsequently approved for the treatment of breast cancer.
Nowadays, paclitaxel has been widely used to treat a variety of malignant tumors, including breast cancer, lung cancer, ovarian cancer and Kaposi's sarcoma. In addition, the efficacy of paclitaxel on other tumors is being further studied, and experiments have proved that it also has potential efficacy on other tumors.
The US Food and Drug Administration has also obtained a lot of information about the clinical efficacy and side effects of paclitaxel. Paclitaxel is the best drug to treat ovarian cancer and breast cancer, and its price is very expensive. The market price is 4800 USD/gram.
Moreover, its natural resources-Taxus chinensis and East African Podocarpus (1999)-grow very slowly, with limited quantity and very low content of effective components. At first, all the yew used for treatment came from Pacific yew. It takes a 600-year-old yew tree to treat a patient.
Taxol and its anticancer homologous derivatives can now be prepared by chemical semisynthesis of its precursors. These precursors include 10- deacetylbaccatin III, baccatin III, 10- deacetylpaclitaxel, 10- deacetyl cephalomannine, 7- valeraldehyde-10- deacetyl paclitaxel, etc.
All these precursors can be isolated from Taxus chinensis. At the same time, another semi-synthetic chemical product, paclitaxel, which has a good therapeutic effect on ovarian cancer, is produced by Rhone-Poulenc Rorer and approved by the US Food and Drug Administration as a therapeutic drug for refractory malignant ovarian cancer.
These studies have alleviated the shortage of drug sources to some extent, but we still have a long way to go to solve it. A Brief History of Paclitaxel 1958 American National Cancer Institute extracts anticancer substances from plants all over the world.
Taxol was found in Taxus chinensis 197 1 year, and its anticancer mechanism is unique. 1992, the United States * * * transferred the patent to Squibb, and paclitaxel came out.
1994 paclitaxel became the global sales champion of anticancer drugs. In 2000, the sales volume of paclitaxel reached10 billion (the supply of raw materials did not increase further). In 2002, the central government issued a document prohibiting the felling of wild yew and encouraging artificial planting.
Squibb's patent expired in 2004, and more pharmaceutical companies around the world intervened in the production of paclitaxel. In 2004, Huayuan started to operate the Taxus chinensis project and set up a taxol refining and processing plant directly under it, aiming to become the largest Taxus chinensis base in China and even Asia.
In 2005, the central government issued a document again to carry out a nationwide survey of Taxus resources and encourage planting. In 2005, the project was invested by individual investors.
4. The synthetic method of paclitaxel and the synthetic method of historical paclitaxel:
1 plant tissue culture
Plant tissue culture uses the totipotency of plant cells, and can use tender stems, needles, bark, cambium, aril and embryo of Taxus plants as explants for culture, thus forming a large number of extraction raw materials. At present, there are many reports at home and abroad, and remarkable results have been achieved.
2 Microbial production
A parasitic fungus (Taxomyces andreanae) isolated from the phloem of Taxus brevifolia by Stierle et al. can produce paclitaxel and its related economic products in a specific medium, but it has not been applied to production at present because of its extremely low yield. By changing culture conditions and applying recombinant DNA technology, it is expected to improve the yield of paclitaxel.
Because roots are organs with high taxol content except bark, people use Agrobacterium rhizogenes to infect explants of Taxus plants to induce roots, and try to produce taxol through this culture system, because this culture system does not need exogenous hormones, and it has attracted much attention because of its fast hairy roots and stable genetic traits.
It will be more meaningful than plant research to actively search for microorganisms that can synthesize paclitaxel or its analogues, locate key enzymes and clone related genes from microbial synthesis routes.
3. Synthesis by bioengineering method
Large-scale production of taxol by bioengineering is to cultivate and screen strains that can produce taxol in large quantities, and to produce taxol in culture medium through continuous expansion of culture without cutting down the few remaining Taxus trees in nature.
Example At present, a taxol-producing strain named HQD33 has been isolated and screened from the bark of a hundred-year-old Taxus chinensis, and then its gene structure was mutated and optimized by many chemical and physical methods, and then it was bioengineered, and finally a high-yield strain containing 448.52 micrograms of taxol per liter of culture medium was cultivated and constructed.
4 artificial semi-synthesis
In order to protect the precious Taxus resources and avoid the destruction of resources caused by collecting a large number of Taxus bark, the goal should be to produce taxol from renewable resources. Bristol-Myers Squibb Company successfully extracted primary raw materials from renewable materials such as branches and leaves of Taxus chinensis in 1994 on the premise of fully ensuring the quality of taxol products, and then produced taxol by artificial semi-synthesis. Its semi-synthetic production method has been approved by FDA. Since then, Taxus Pacific is no longer destructively collected, and the sustainable production and supply of paclitaxel has also been guaranteed.
The molecular structure of organic taxol is complex, with special tricyclic [6+8+6] carbon skeleton, bridgehead double bonds and many oxygen-containing substituents. Its total synthesis has attracted the interest of many organic chemists at home and abroad. It is rare that more than 30 research groups have participated in the research. After more than 20 years' efforts, two research groups, R.A.Holton and K.C.Nicolaou in the United States, completed the total synthesis of paclitaxel in 1994.
Later, there were S.T. Danishevski (1996), P.A. Wen-De (1997), T. Mukai Mountain (1998) and I. Kuwaji-Ma (1998). Although the six synthetic routes are different, they all have excellent synthetic strategies, which have raised the chemistry of natural organic synthesis to a new height.
As for the history of synthesis, there is no specific summary, it is not easy to find!