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Chemistry 150, Fall 2008 “The Pain Inducing, Cancer Remedy”: The Occurance, Bioactivity, Biosynthesis, and Synthesis of Vincristine Vincristine was approved by the Food and Drug Administration (FDA) in 1984. It is available in the trade under the names Oncovin, Vincasar, and Vincrex. This drug was previously known as leurocristine (LCR). The derivatives of the vinca alkaloids include vincristine, vinblastine, vindesine, and vinopocetine. II. Biological Activity Vincent Ting, Fall 2008 Introduction Vincristine is an anti-neoplastic drug found in the Madagascar periwinkle (Catharanthus roseus). It is clinically used to treat a range of cancers including various lymphomas and sarcomas, advanced testicular cancer, breast cancer and acute leukemia.12 Vincristine belongs to a group of bisindole alkaloids derived from tryptophan. Vincristine disrupts the formation of microtubules cells, which inhibits the replication of cancer cells. It is generally used as a chemotherapy drug for cancer patients to slow the growth of cancer cells. Vincristine sulfate is widely used to treat leukemia, malignant lymphomas, meuroblastoma, Hodgkin’s disease, Wilm’s tumor, and many other cancers. N N H OH CO2Me MeO Vincristine N H OAc OH N H CO2Me CHO Figure 1. Vincristine, used to treat various types of cancer and can be found in the Madagascar periwinkle. I. Occurrence Vincristine is found in Catharanthus roseus, more commonly known as the Madagascar periwinkle. This plant was formerly named Vinca roseus. The genus Catharanthus has eight species, seven of which are endemic to the island of Madagascar and the eighth is found in the subcontinent of India. In the wild, the Catharanthus roseus is an endangered plant due to its habitat destruction. However, it is widely cultivated and globally grown in tropical and subtropical areas. Figure 2. Catharanthus roseus. source (http://www.biologie. uni-regensburg.de/Botanik/Schoenfelder/kanaren/images/ Catharanthus_roseus.jpg) Figure 3. Vial of Vincristine. Source (http://www.vghks.gov. tw/ph/%B3B%A4%E8%B6%B0/drug/vincristine.files/image0 04.jpg) Vincristine can only be administered intravenously and if introduced into the spinal cord fluid, it ensures almost absolute death. Patients experience paresthesias because vincristine causes damage to small nerve fibers carrying the sensations of pain and temperature. Another side affect would be a disturbance of nerve fibers that help muscles around the colon that move stool, which means that the patient will experience constipation. Toxic effects may include numbness, pain, tingling, headaches, rashes, a change in blood pressure, dizziness, nausea, vomiting, hearing problems, and hair loss. Effects are more common to those with poor liver function. Short-term pretreatment with vincristine expresses impressive protective effects in cultured adult mouse myocytes subjected to acute oxidative stress.3 However, it can damage the patient’s bone marrow or because of its neurotoxicological effects, so the amount administered is severely limited.2 The organism expresses thermo allodyna and mechanical hypersensitivity after taking vincristine. Vincristine expresses unfavourable side effects, but is very efficient in treating various types of cancers. Vinca alkaloids inhibit microtubule formation by binding to tubulin.6 All four clinically available vinca alkaloids cause neuropathy, but vincristine has the lowest risk for peripheral neuropathy. Similarly, vinblastine has the highest risk of peripheral neuropathy and the only difference N-methyl group rather than N-formyl on the vindoline fragment. vincristine Chemistry 150, Fall 2008 can be an oxidized product from vinblastine. Vinca alkaloids have various beneficial properties besides being anti-mitotic and anti-microtuble drugs. Derivatives of vinca alkaloids have shown to be immunosuppressive drugs and nootropic drugs. III. Biosynthesis Vincristine belongs in a group of alkaloids that derive from tryptophan. The structure of vincristine is derived by coupling of two alkaloids, catharanthine and vindoline. The biosynthesis of vincristine is summarized in Figure 4. First, catharanthine (1) is oxidised by a peroxidise catalyst (2), which forms a peroxide which acts as a leaving group. When the peroxide leaves, the carbon-carbon bond is broken and the intermediate electrophilic ion (3) is attacked by the nucleophilic vindoline (4). The molecule is then reduced in the dihydropyridinium ring by NADH-dependent 1,4-addition, giving the substrate for hydroxylation (7). Finally, reduction by NADH yields vincristine. N N H OH O peroxidase CF3CO N H CO2Me 2 O N m-chloroperbenzoic acid N N N H CO2Me charged oxygen to form catharanthine N-oxide (9). When the carbon-carbon bond is broken by the trifluoroacetic anhydride, the intermediate electrophilic ion (10) is attacked by the nucleophilic vindoline (11). The substrate is then reduced in the dihydropyridinium ring and oxidized by ferric chloride and oxygen (14). Finally, vincristine is formed by reduction by sodium borohydride. There are other methods for the synthesis of vincristine. The synthesis of (+)-vincristine has been accomplished through a stereoselective coupling of demethylvindoline and the eleven-membered carbomethoxyverbanamine precursor.4 The oxidation of 17-hydroxy-11-methoxytabersonine, followed by regioselective acetylation with mixed anhydride method yielded demethylvindoline.4 Fukuyama’s first de novo syntheses of these alkaloids was published in 2002 and 2004, but researchers continue to find new and efficient methods that allow for the assembly of key substructures of vincristine. N H CO2Me CO2Me 9 8, catharanthine 1, catharanthine (CF3CO)2O N N N 5 N H N H H CO2Me N 3 V CO2Me OAc OH N H CO2Me MeO CHO 4, vindoline (V) H NADH N H N H 10 H N V CO2Me CO2Me N OAc OH N H CO2Me MeO CHO 11, vindoline (V) H 12 CONH2 N N N H N [O] V CO2Me 7 6 NaO2C V OH CO2Me N H N N H NADH N V CO2Me OH CO2Me MeO 14 NaBH4 N H N OAc OH N H CO2Me CHO N H OH CO2Me Vincristine Figure 4. Biosynthesis of Vincristine. V OH CO2Me N H 13 N N H FeCl3 O2 MeO 8 Vincristine IV. Synthesis Like the biosynthesis, the synthesis of vincristine is composed of catharanthine and vindoline. Catharanthine is catalyzed by m-chloroperbenzoic acid which adds a negatively Figure 5. Synthesis of Vincristine.8 N H OAc OH N H CO2Me CHO Chemistry 150, Fall 2008 Conclusion Vincristine is a very interesting and useful drug. Derived from catharanthine and vindoline through the alkaloid pathway, it is used to treat various cancers by disrupting the formation of microtubules cells, which inhibits the replication of cancer cells. This drug can only be introduced intravenously and causes slight nerve damage. Vinca alkaloids possess beneficial properties such as slow cancer cell growth, yet they have slight toxic effects and occasionally cause the patient to be in pain. Since vincristine expresses the lowest risk of peripheral neuropathy out of the four vinca alkaloids, the positive effects outweigh the negative. Vincristine is a useful drug used to treat various lymphomas and sarcomas, advanced testicular cancer, breast cancer, acute leukemia, meuroblastoma, and other types of cancers. The development of an easy synthesis for vincristine is important and researchers continue to find new and efficient for the synthesis of vincristine. References ________________ 1 Thibault, K.; Van Steenwinckel, J.; Brisorgueil, M.-J.; Fischer, J.; Hamon, M.; Calvino, B.; Conrath, M. Serotonin 5HT2A receptor involvement and Fos expression at the spinal level in vincristine-induced neuropathy in the rat. Pain 2008, 140, 305-322. 2 Harvey, M. J.; Banwell, M. G.; Lupton, D. W. The synthesis of compounds related to the indole-indoline core of the vinca alkaloids (+)-vinblastine and (+)-vincristine. Tetrahedron Lett. 2008, 49, 4780-4783. 3 Chatterjee, K.; Zhang, J.; Honbo, N.; Simonis, U.; Shaw, R.; Karliner, J. S. Acute vincristine pretreatment protects adult mouse cardiac myocytes from oxidative stress. J. Mol. Cell. Cardiol. 2007, 43, 327-336. 4 Kuboyama, T.; Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Stereocontrolled total synthesis of (+)-vincristine. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11966-11970. 5 Lynch, J. J., III; Wade, C. L.; Zhong, C. M.; Mikusa, J. P.; Honore, P. Attenuation of mechanical allodynia by clinically utilized drugs in a rat chemotherapy-induced neuropathic pain model. Pain 2004, 110, 56-63. 6 Takigawa, N.; Tanimoto, M. Vinca alkaloid and MDR1. Gan to Kagaku Ryoho 2008, 35, 1086-1089. 7 Jordan, M. A.; Horwitz, S. B.; Lobert, S.; Correia, J. J. Exploring the mechanisms of action of the novel microtubule inhibitor vinflunine. Semin. Oncol. 2008, 35, S6-S12. 8 Dewick, P. Medicinal Natural Products:A Biosynthetic Approach, 2nd ed., Wiley&Sons: West Sussex, England, 2001, p 350-355.