Combretastatins structures

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). 

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. 

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. 

Chart 1 Chemical structures of colchicine (1), combretastatin A-4 (2), podophyllotoxin (3), vinblastine (4) and vincristine (5)... 

In 2000, Macdonald and co-workers reported CoMFA-based 3D-QSAR models able to describe the binding of different structural types of combretastatins to the colchicine binding site [26], The study resulted in the first significantly predictive models for the class of combretastatins. 

QSAR CSI encompassing several structural classes Biophores for colchicinoids, podophyllotoxins and combretastatins, indicating the main structural features responsible for the activity of compounds [25]... 

Pettit GR, Singh SB, Hamel E, Lin CM, Alberts DS, Garcia-Kendall D. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 1989 45 209-211. 

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. 

Stilbenophanes. During a research directed at the synthesis and evaluation of new cytotoxic agents based on natural products, several macrocyclic derivatives of combretastatin A-4 and related compounds were investigated. Fig. (5) [22]. These compounds are poly oxygenated stilbenophanes macrocyclized through a polymethylene(polyether) chain sharing in part the structure of crownophanes. 

A wide range of structural analogues have been reported, which include substitution of the A- and/or B-ring in the combretastatin framework with different carbo- and heteroeycles. Some examples are reported below. 

Furazan 1,2,5-oxadiazole) derivatives Combretafurazan, Fig. (11)), have been recently synthesized via a Mitsunobu reaction of vicinal dioximes [33]. Combretafurazans are more potent in vitro cytotoxic compounds compared to combretastatins in neuroblastoma cells, yet maintaining similar structure-activity relationship and pharmacodynamic profiles. 

The synthesis of many combretastatin analogues (e.g., 18a, 18b, and 18c) clearly illustrates the power of a relatively simple natural product structure to spawn a prolific output of medicinal and combinatorial chem-... 

The family of colchicines-site binders includes compounds of diverse structure unified by interference with the colchicine binding epitope. The respective compounds can be clustered according to their chemical structure mainly into I) colchicines and compounds with colchicine like substructures, II) combretastatins and phenstatins, III) compounds having an indole core structure, IV) quinolones, V) sulphonamidcs and VI) naturally occurring as well as synthetic compounds. 

Fig. (3). Structures of flavonoids that show interference with tubulin polymerization and antimitotic compounds structurally correlated with the former. A Flavone B. C Synthetic chalcones D Combretastatin A-4 E Colchicine.

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