VincristineVincristineMichael DoeMichael DoeCHEM 23202CHEM 23202

OverviewOverview

I. Physical PropertiesI. Physical Properties II. SynthesisII. Synthesis III. CharacterizationIII. Characterization IV. History and UsesIV. History and Uses V. How it worksV. How it works

General InformationGeneral Information22

CAS Number: 57-22-7CAS Number: 57-22-7 Molecular Formula: CMolecular Formula: C4646HH5656NN44OO1010

Molecular Weight: 824.97Molecular Weight: 824.97 Melting Point: 218-220Melting Point: 218-220°C°C Clear liquidClear liquid

(taken by injection)(taken by injection)

Synthesis from a Natural Synthesis from a Natural SourceSource

Vincristine has two natural sources: Vincristine has two natural sources: Catharanthus roseus (Vinca rosea), Catharanthus roseus (Vinca rosea), the Madagascar periwinkle, andthe Madagascar periwinkle, and

Tabernaemontana pachysiphonTabernaemontana pachysiphon This yield from the Madagascar This yield from the Madagascar

periwinkle is less than 1periwinkle is less than 1μμg/g g/g (.0003%)(.0003%)66

Synthesis from vinblastineSynthesis from vinblastine

H2CrO4

Ethyl Acetate2 hours, -83- -

25°C

80-90% yield5

• This is the easiest and most common method of synthesis, as well as one can give high yields

Synthetic ProductionSynthetic Production

Discovered in 2004First route to make synthetic vincristine6

SpectroscopySpectroscopy Mass SpectrumMass Spectrum44: M+1=825: M+1=825 UV SpectrumUV Spectrum11: 220, 255, 296 nm: 220, 255, 296 nm IR SpectrumIR Spectrum66: 3445, 2924, 2852, : 3445, 2924, 2852,

1740, 1681, 1597, 1498, 1458, 1369, 1740, 1681, 1597, 1498, 1458, 1369, 1230, 1033, 747 cm-1 1230, 1033, 747 cm-1

History and UsesHistory and Uses Discovered in 1953 by Robert L. Discovered in 1953 by Robert L.

Noble, and cleared by the FDA in 1963 Noble, and cleared by the FDA in 1963 as Oncovin, marketed by Eli Lilly and as Oncovin, marketed by Eli Lilly and Co.Co.

Used to treat acute leukemias and all Used to treat acute leukemias and all lymphomaslymphomas

Side effects include nervous system Side effects include nervous system damage and constipationdamage and constipation

Work is being done to develop more Work is being done to develop more effective derivatives with fewer side effective derivatives with fewer side effectseffects88

How it worksHow it works Stops division of cellsStops division of cells Enters cell during mitosis and blocks Enters cell during mitosis and blocks

formation of microtubules of the formation of microtubules of the mitotic spindle during metaphasemitotic spindle during metaphase3,73,7

BibliographyBibliography (1) Anonymous Vincristine. In (1) Anonymous Vincristine. In The Merck index: an encyclopedia of chemicals, drugs, The Merck index: an encyclopedia of chemicals, drugs,

and biologicals; and biologicals; O'Neil, M. J., Ed.; Merck: Whitehouse Station, NJ, 2006; pp 1717-O'Neil, M. J., Ed.; Merck: Whitehouse Station, NJ, 2006; pp 1717-1718. 1718.

(2) Anonymous Chemfinder.com Database and Internet Searching. (2) Anonymous Chemfinder.com Database and Internet Searching. http://chemfinder.cambridgesoft.com (accessed Jan. 22, 2007). (accessed Jan. 22, 2007).

(3) Anonymous Overview: The Mitotic Spindle. (3) Anonymous Overview: The Mitotic Spindle. http://www.sinauer.com/pdf/nsp-cellcycle-6-0.pdf (accessed Apr. 15, 2007). (accessed Apr. 15, 2007).

(4) Choi, Y. H.; Kim, J.; Yoo, K. Supercritical Fluid Extraction and Liquid (4) Choi, Y. H.; Kim, J.; Yoo, K. Supercritical Fluid Extraction and Liquid Chromatography-Electrospray Mass Analysis of Vinblastine from Chromatography-Electrospray Mass Analysis of Vinblastine from Catharanthus roseusCatharanthus roseus. . Chem. Pharm. Bull. Chem. Pharm. Bull. 20022002, 50, 1294--1296. , 50, 1294--1296.

(5) Huhtikangas, A.; Laakso, I.; Seppaenen-Laakso, T.; Verma, A. Patent Application (5) Huhtikangas, A.; Laakso, I.; Seppaenen-Laakso, T.; Verma, A. Patent Application Country: Application: FI; Patent Country: FI Patent 107924, 2001. Country: Application: FI; Patent Country: FI Patent 107924, 2001.

(6) Kuboyama, T.; Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Stereocontrolled total (6) Kuboyama, T.; Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Stereocontrolled total synthesis of (+)-vincristine. synthesis of (+)-vincristine. Proc. Natl. Acad. Sci. U. S. A. Proc. Natl. Acad. Sci. U. S. A. 20042004, 101, 11966-11970. , 101, 11966-11970.

(7) Lurie, P. M.; Manaster, J.; Stryckmans, P. A.; Vamecq, G. Mode of Action of (7) Lurie, P. M.; Manaster, J.; Stryckmans, P. A.; Vamecq, G. Mode of Action of Chemotherapy Chemotherapy in vivoin vivo on Human Acute Leukemia--II. Vincristine. on Human Acute Leukemia--II. Vincristine. Europ. J. Cancer Europ. J. Cancer 19731973, 9, 613--620. , 9, 613--620.

(8) Szabo, L.; Bolcskei, H.; Eszter, B.; Mak, M.; Szantay, C. Synthesis of vinca (8) Szabo, L.; Bolcskei, H.; Eszter, B.; Mak, M.; Szantay, C. Synthesis of vinca alkaloids and related compounds, Part XCV: Nitration study of vinblastine-type alkaloids and related compounds, Part XCV: Nitration study of vinblastine-type bisindole alkaloids. bisindole alkaloids. Arch. Pharm. Pharm. Med. Chem. Arch. Pharm. Pharm. Med. Chem. 20012001, 334, 339--405. , 334, 339--405.