Vinblastine

Vinblastine

Systematic (IUPAC) name
dimethyl (2β,3β,4β,5α,12β,19α)- 15-[(5S,9S)- 5-ethyl- 5-hydroxy- 9-(methoxycarbonyl)
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682848
Pregnancy cat.	D(AU) D(US)
Legal status	POM (UK) ℞-only (US)
Routes	Exclusively intravenous
Pharmacokinetic data
Bioavailability	n/a
Metabolism	Hepatic (CYP3A4-mediated)
Half-life	24.8 hours (terminal)
Excretion	Biliary and renal
Identifiers
CAS number	865-21-4 Y
ATC code	L01CA01
PubChem	CID 241903
DrugBank	APRD00708
ChemSpider	211446 Y
UNII	5V9KLZ54CY Y
KEGG	D08675 Y
ChEBI	CHEBI:27375 Y
ChEMBL	CHEMBL159 N
Synonyms	vincaleukoblastine
Chemical data
Formula	C46H58N4O9
Mol. mass	810.974 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C46H58N4O9/c1-8-42(54)23-28-24-45(40(52)57-6,36-30(15-19-49(25-28)26-42)29-13-10-11-14-33(29)47-36) N Key:JXLYSJRDGCGARV-XQKSVPLYSA-N Y
N(what is this?)  (verify)

Vinblastine is an antimicrotubule drug used to treat certain kinds of cancer, including Hodgkin's lymphoma, non-small cell lung cancer, breast cancer, head and neck cancer, and testicular cancer. It is also used to treat Langerhan cell histiocytosis.

History

Vinblastine was first isolated by Robert Noble and Charles Thomas Beer from the Madagascar periwinkle plant. Vinblastine's utility as a chemotherapeutic agent was first discovered when it was crushed into a tea. Consumption of the tea led to a decreased number of white blood cells; therefore, it was hypothesized that vinblastine might be effective against cancers of the white blood cells such as lymphoma.

Pharmacology

Vinblastine is a vinca alkaloid and a chemical analogue of vincristine. It binds tubulin, thereby inhibiting the assembly of microtubules. It is M phase cell cycle specific since microtubules are a component of the mitotic spindle and the kinetochore which are necessary for the separation of chromosomes during anaphase of mitosis. Toxicities include bone marrow suppression (which is dose-limiting), gastrointestinal toxicity, potent vesicant (blister-forming) activity, and extravasation injury (forms deep ulcers). Vinblastine paracrystals may be composed of tightly-packed unpolymerized tubulin or microtubules.^[1]

Vinblastine is reported to be an effective component of certain chemotherapy regimens, particularly when used with bleomycin, and methotrexate in VBM chemotherapy for Stage IA or IIA Hodgkin lymphomas. The inclusion of vinblastine allows for lower dosese of bleomycin and reduced overall toxicity with larger resting periods between chemotherapy cycles. ^[2]

Mechanism of Action

Microtubule disruptive drugs like vinblastine, colcemid, nocodazole have been reported to act by two mechanisms.^[3] At very low concentrations they suppress microtubule dynamics and at higher concentrations they reduce microtubule polymer mass. Recent findings indicate that they also produce microtubule fragments by stimulating microtubule minus-end detachment from their organizing centers. Dose-response studies further indicate that enhanced microtubule detachment from spindle poles correlate best with cytotoxicity.^[4]

Isolation and Synthesis

Vinblastine may be isolated from the Madagascar Periwinkle (Catharanthus roseus), along with several of its precursors- catharanthine and vindoline. Extraction is costly and yields of vinblastine and its precursors are low. Enantioselective synthesis has been of considerable interest in recent years, as the natural mixture of isomers is not an economical source for the required C16’S, C14’R stereochemistry of biologically active vinblastine. Initially, the approach depends upon an enantioselective Sharpless epoxidation, which sets the stereochemistry at C20. The desired configuration around C16 and C14 can then be fixed during the ensuing steps. In this pathway, vinblastine is constructed by a series of cyclization and coupling reactions which create the required stereochemistry. The overall yield may be as great as 22%, which makes this synthetic approach more attractive than extraction from natural sources, whose overall yield is about 10 %. ^[5] Stereochemistry is controlled through a mixture of chiral agents (Sharpless catalysts), and reaction conditions (temperature, and selected enantiopure starting materials). ^[6]

Indications

Vinblastine is a component of a number of chemotherapy regimens, including ABVD for Hodgkin lymphoma. It is also used to treat histiocytosis according to the established protocols of the Histiocytosis Association of America.

See also

• Rosy Periwinkle
• ABVD

Footnotes

1. ^ Starling D (1 January 1976). "Two ultrastructurally distinct tubulin paracrystals induced in sea-urchin eggs by vinblastine sulphate.". J Cell Sci 20 (1): 79–89. PMID 942954. http://jcs.biologists.org/cgi/reprint/20/1/79. 
2. ^ Goppi, P. G.; et al.. "Vinblastine, Bleomycin, and Methotrexate Chemotherapy plus Irradiation for Patients with Early-Stage, Favorable Hodgkin Lymphoma". CANCER. 98 (11): 2393–2401. 
3. ^ Jordan MA, Leslie W (Apr 4, 2004). "Microtubules as a target for anticancer drugs". Nat Rev Cancer 4 (4): 253–65. doi:10.1038/nrc1317. PMID 15057285. 
4. ^ Yang H, Ganguly A, Cabral F (Aug 9, 2010). "Inhibition of cell migration and cell division correlate with distinct effects of microtubule inhibiting drugs". J. Biol. Chem. 285 (42): 32242–50. doi:10.1074/jbc.M110.160820. PMC 2952225. PMID 20696757. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2952225. 
5. ^ Kuehne, M. E.; Matson, P. A.; and Bornmann, W. G. (April 20, 1990). "Enantioselective Syntheses of Vinblastine, Leurosidine, Vincovaline, and 20'-epi –Vincovaline". J. Org. Chem. 56 (2): 513–528. 
6. ^ Yokoshima, S; Tokuyama, H; and Fukuyama, T.. "Total Synthesis of (+)-Vinblastine: Control of the Stereochemistry at C18′". The Chemical Record. 10: 101–118.