Combretastatin

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Combretastatin
Systematic (IUPAC) name
1-(3,4,5-trimethoxyphenyl)-2-(3'-hydroxy-4'-methoxyphenyl)ethene 3,4,5-trimethoxy-3'-hydroxy-4'-methoxystilbene
Identifiers
CAS number	117048-59-6
ATC code	?
PubChem	?
Chemical data
Formula	C₁₈H₂₀O₅
Mol. mass	316.348
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	X
Legal status
Routes	Oral tablets

1 Natural combretastatins
2 Biological function
3 Synthesis
4 References
5 External links

[edit] Natural combretastatins

A variety of different natural combretastatin molecules are present in the bark of Combretum caffrum commonly known as South African Bush Willow. Of the natural products presently known combretastatin A-4 is the most potent in regards to both tubulin binding ability and cytotoxicity. Combretastatin A-1 is also a potent cytotoxic agent.

Molecules that fall into the combretastatin family generally share 3 common structural features: a trimethoxy "A" ring, a "B" ring containing substitutents often at C3' and C4', and an ethene bridge between the two rings which provides necessary structural rigidity. Molecules with C3' amino and hydroxyl substituents are very active, and molecules with C4' hydroxyl or methoxy substituents are also cytotoxic.

[edit] Biological function

Members of the combretastatin family possess varying ability to cause vascular disruption in tumor cells. Combretastatin binds to the β-subunit of tubulin at what is called the colchicine site, referring to the previously discovered vasculature disrupting agent colchicine. Inhibition of tubulin polymerization prevents cancer cells from producing microtubules. Microtubules are essential to cytoskeleton production, intercellular movement, cell movement, and formation of the mitotic spindle used in chromosome segregation and cellular division.

[edit] Synthesis

A variety of possible routes to the combretastatin skeleton are possible. One reasonably easy synthesis is as follows:

1-methylbromo-3,4,5-trimethoxybenzene undergoes an SN2 reaction with triphenylphosphine.
The triphenylphosphine product is coupled to a benzaldehyde B ring possessing the desired substitutents using a wittig reaction.
The wittig reaction produces both E and Z isomers. Generally cis-combretastatin possesses significantly improved ability to inhibit tubulin polymerization as well as cytotoxicity.

[edit] References

Sackett, D; Varma, J. Molecular mechanism of Colchicine action: induced local unfolding of beta tubulin Biochemistry, 1993, 32, 13560-13565.

Beauregard, D; Hill, S; Chaplin, D; Brindle, K. The susceptibility of tumors to the antivascular drug combretastatin A4 phosphate correlated with vascular permeability Cancer Research, 2001, 61, 6811-6815.

Griggs, J; Metcalfe, J. C; Hesketh, R. Targeting tumor vasculature: the development of combretastatin A4 Lancet Oncol, 2001, 2, 82-87.

Hadfield, J; Ducki, S; Hirts, N; McGown, A. Tubulin and microtubules as targets for anticancer drugs Progress in Cell Cycle Research, 2003, 5, 309-325.

Pandit, Bulbul; Sun, Yanjun; Chen, Ping; Sackett, Dan; Hu, Zhigen; et al. Structure-activity-relationship studies of conformationally restricted analogs of combretastatin A-4 derived from SU5416 Bioorganic and Medicinal Chem, 2006, 14, 6492-6501

Pati, H; Taherbhai, Z; Forrest, L; Wicks, M; Bailey, S; Staples, A; et al. A Stereospecific Route for the Preparation of Trans-Combretastatin Analogs: Synthesis and Cytotoxicity Letters in Drug Design & Discovery, 2004, 1, 275-278.

Monaco, R. R; Gardiner, W. C; Kirschner, S. Semiemperical Studies of Ring Twisting in cis-Stilbene and Related Biomolecules International Journal of Quantum Chemistry, 1999, 71, 57-62.

Maya, Ana B. S; Perez-Melero, Concepcion; Mateo, Carmen; Alonso, Dulce; Fernandez, Jose Luis; et al. Further Napthylcombretastatins. An Investigation on the Role of the Naphthalene Moiety J. Med. Chem, 2005, 48, 556-568.

Monk, Keith A; Siles, Rogelio; Hadimani, Mallinath B; Mugabe, Benon E; et al. Design, Synthesis, and Biological Evaluation of Combretastatin Nitrogen-Containing Derivatives as Inhibitors of Tubulin Assembly and Vascular Disrupting Agents Bioorg. Med. Chem, 2006, 14, 3231-3244.