Combretastatin

The combretasatins are a class of natural stilbenoid phenols. A variety of different natural combretastatin molecules are present in the bark of Combretum caffrum, commonly known as South African Bush Willow.

Natural combretastatins
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. 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.

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.

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-derived 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.