Colchicine binding site inhibitors

Combretastatins are a class of compounds originally derived from the African Willow tree (Combretum caffrum) and are powerful reversible inhibitors of tubulin polymerization. This class of molecules has been shown to bind to the colchicine binding site of tubulin, by the same mode of action as mentioned above (Sect. 1.2). Combretastatins consist of a ris-slilbcnc core structure. To date, there have been several compounds that have shown promise as potential anticancer drugs. However, development of these compounds as anticancer agents is limited by issues of chemical stability, bioavailibilty, toxicity, and solubility. 

A second group of tubulin inhibitors is represented by compounds exhibiting the combretastatin structure. Combretastatin (5) itself, as well as combretastatins A-l (5a), A-4 (5b) and A-2 (5d), have first been extracted from a South African tree Combretum caffrum by Pettit et al., depicting affinity to the colchicine binding site [28], Syntheses of various analogues of this simple molecule, thereafter, have been reported [16,29, 30] (see also Scheme 1). 

THE FAMILY OF COLCHICINE-SITE BINDING TUBULIN INHIBITORS... 

Vinca alkaloids (vincristine, vinblastine, vinorelbine) are derived from the periwinkle plant (Vinca rosea). These agents work by binding to tubulin at a site different than colchicine or paclitaxel. They block polymerization, which prevents the formation of the mitotic spindle, and are used as antineoplastic agents. Taxanes produce a stabilization of microtubules similar to colchicine, but by a different mechanism, and also halt cells in metaphase. Paclitaxel (taxol) is the taxane used clinically. It is derived from the bark of the pacific yew. Taxol disrupts several microtubule-based functions as completely as inhibitors of polymerization, emphasizing the importance of assembly/disassembly balance in microtubule function. Recently, it has been found that paclitaxel also binds to and inhibits the function of a protein called bcl-2, an inhibitor of one or more pathways involved in mediating apoptosis. PaclitaxeTs interference with this function promotes apoptosis in addition to its microtubule-related inhibition of cell division. 

The first compound of the taxanes series, paclitaxel (Taxol), was isolated from the bark of the Western yew tree in 1971. It and its congenic, the semisynthetic docetaxel (Taxotere), exhibit unique pharmacological actions as inhibitors of mitosis, differing from the vinca alkaloids and colchicine derivatives in that they bind to a different site on P-tubulin and promote rather than inhibit microtubule formation. The drugs have a central role in the therapy of ovarian, breast, lung, esophageal, bladder, and head and neck cancers. 

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