Antimitotic agents combretastatin

Lin CM, Singh SB, Chu PS, Dempcy RO, Schmidt JM, Pettit GR, Hamel E. Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin a structure-activity study. Mol. Pharmacol. 1988 34 200-208. 

The combretastatins are a group of antimitotic agents isolated from the bark of the South African tree Combretum caffrum. A novel and highly stereoselective total synthesis of both the c/s and trans isomers of combretastatin A-4 was developed by J.A. Hadfield and co-workers.The (Z)-stereoisomer was prepared using the Perkin reaction as the key step in which 3,4,5-trimethoxyphenylacetic acid and 3-hydroxy-4-methoxbenzaldehyde was heated with triethylamine and acetic anhydride at reflux for several hours. The a,p-unsaturated acid was isolated in good yield after acidification and had the expected ( ) stereochemistry. Decarboxylation of this acid was effected by heating it with copper powder in quinoline to afford the natural product (Z)-combretastatin A-4. 

The Vinca alkaloids and some other antimitotic agents thus represent another class of agents that can selectively inhibit tumor blood flow by a mechanism that is distinct from that of TNF or TNF inducers such as FAA and DMXAA. Combretastatin A4, another antimitotic agent, appears to have a vascular basis for its action (81) and is currently a candidate for clinical trial. The mechanism of action of mitotic inhibitors is not well understood, but may result from their effects on vascular endothelial cells (82). 

Methoxy indole-containing combretastatin derivatives, (I), and prodrugs, (II), prepared by Pinney (2) were found effective as antimitotic and antitubulin polymerization agents and used in the selective destruction of tumor cell vasculature. 

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