Combretastatin

Brown T, Holt H Jr, Lee M (2006) Synthesis of Biologically Active Heterocyclic StUbene and Chalcone Analogs of Combretastatin. 2 1-51... 

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. 

The most famous of these compounds is combretastatin A-4 (CA-4,7), isolated by Pettit et al. in 1989 [30]. Pettit s research led to the isolation and structural determination of a series of phenanthrenes, dihydrophenanthrene, stilbene, and bibenzyl compounds [31]. CA-4 (7), alongside CA-1 (8), was found to be an extremely active inhibitor of tubulin polymerization [30,32]. The major problems associated with these compounds were poor bioavailability and low aqueous solubility [33,34], and hence, research in the field was turned to designing better alternatives with the hope of eradicating the negative properties of these potent compounds. 

There are a number of other compounds that make modifications to the A- and B-ring of the combretastatin derivatives however, these molecules are outside the scope of this review. 

Davies et al. describe the preparation of both oxazole- and thiazole-containing derivatives of combretastatin. By formation of the ketoamide intermediate 60, in a 54% yield (Scheme 14), both classes of compounds may be obtained by altering the last step of the reaction [58]. To produce the oxazole 61 a cyclo-dehydration reaction was performed using triphenylphosphine-iodine-triethylamine, and the thiazole compound 62 was formed by thiona-tion using Lawesson s reagent, with an excellent yield (94%). 

The aforementioned section described the synthesis of a wide range of biologically important heterocyclic derivatives of combretastatin. The next part of this chapter will focus on the synthesis of heterocyclic chalcone derivatives. 

There are considerably fewer examples of heterocyclic chalcone analogs of combretastatin than in the heterocyclic stilbene derivative category. Of these,... 

The synthesis of biologically important heterocyclic stilbene and chalcone derivatives of combretastatins has been discussed. Combretastatins have been shown to be inhibitors of tubulin polymerization. In many cases the compounds described in this chapter were included because of an interesting synthesis or structure, although limited biological data were found. It is the author s opinion that a great number of the compounds contained within this review are worthy of further investigation as potential tubulin binders. 

Combretastatin A-4 Stilbenoid phenol Combretastatin A-4 Oncology Tubulin binding Phase I/imil OXIGENE 644-650... 

Combretastatin A-1 Stilbenoid phenol OXi4503 Oncology Tubulin binding Phase I/II OXiGENE 652-657... 

Escalona-Benz E, Jockovich ME, Murray TG, Hayden B, Hernandez E, Eeuer W, Windle JJ. (2005) Combretastatin A-4 prodrug in the treatment of a murine model of retinoblastoma. Invest Ophthalmol Vis Sci 46 8-11. 

Aprile S, Grosso ED, Grosa G. (2010) Identification of the human UDP-glucuronosyltransferases involved in the glucuronidation of combretastatin A-4. Drug Metab Dispos 38 1141-1146. 

Pettit GR, Temple C, Narayanan VL, Varma R, Simpson MJ, Boyd MR, Rener GA, Bansal N. (1995) Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs. Anticancer Drug Des 10 299-309. 

Young SL, Chaplin DJ. (2004) Combretastatin A4 phosphate Background and current clinical status. Expert Opin Invest Drugs 13 1171-1182. 

Pettit GR, Lippert JW. (2000) Antineoplastic agents 429. Syntheses of the combretastatin A-1 and combretastatin B-1 prodrugs. Anti-Cancer Drug Des 15 203-216. 

---