Combretastatin compounds

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 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. 

Radiolabeled 3-demethyl-3-chloroacetylthiocolchicine with a l4C label in the chloroacetyl moiety (DCTC) was found to be a potent inhibitor of tubulin polymerization and of colchicine binding to tubulin. The reaction was 80-90% inhibited in the presence of saturating, amounts of known antitubulin compounds such as podophyllotoxin, combretastatin A-4, and colchicine itself. The tubulin /3 subunit was labeled 5-6 times faster than the a subunit. Cyanogen bromide digestion of the /3 subunit which had reacted covalently with DCTC indicated that at least three positions in /3-tubulin had reacted with DCTC. Purification and amino acid sequencing of these peptides are in progress (138). 

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

The anticancer compound combretastatin 87 has also been made via a halogen-metal exchange step.79... 

The intramolecular Ullmann condensation was used by D.L. Boqer and co-workers to form the 15-membered macrocyclic ring of the cytotoxic natural product, combretastatin D-2. This compound possesses unusual meta- and paracyciophane subunits, which are also found in a range of antitumor antibiotics. The first approach where the final step was a macrolactonization was unsuccessful, so the researchers chose to form the biaryl ether moiety as the key macrocyciization step. Methyicopper was found to mediate the cyclization and gave moderate yield of the corresponding biaryi ether. Finaiiy boron triiodide mediated demethylation afforded the natural product. 

The relative molecular simplicity of combretastatins and resveratrol, associated with their important anticancer properties, offers promises for the rational design of new chemotherapeutic agents. The interest in these compounds is evident from the great number of papers published every years, covering various aspects, chemical and biological. For this reason in this paper the attention will be focused on Combretastatins. The majority of compounds reported in the paper are in fact considered their derivatives or analogues, albeit some of them, e.g. 3,4,5-trimethoxy-4 -substituted stilbenes have been considered resveratrol analogues. 

As reported above, a substituent at the 3 -position of the B-ring was almost always required for cytotoxic activity. Several derivatives, having different atoms or groups at this position were therefore synthesized and evaluated as potential cancer cell grown inhibitors a selection is reported in the Table 1. In addition, since Combretastatin A-4 is highly lipophilic, and the in vivo lack of efficacy had been ascribed to its poor pharmacokinetics, the 3 -substituent has been often designed not only to improve the therapeutic potential of these compounds, but also to... 

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. 

The finding that the 2-naphthalene moiety is a good surrogate for the isovanillin moiety (4-methoxy-3-hydroxyphenyl), fuelled the search for plausible replacements for the 3 -hydroxy-4 -methoxyphenyl (IsoV) B ring of Combretastatin A-4 other than the 2-naphthyl. Veirious heterocycles were considered, the most conservative choice being the indole ring in compound 14, fig. (7) [24]. 

Even though the introduction of a naphthalene system keeps most of the potency of combretastatins, their low aqueous solubility is a main drawback in order to assay these compounds in vivo. To overcome this problem a new family of analogues replacing the naphthalene moiety by a quinoline or quinoxaline system was synthesized. Fig. (8) [25]. 

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. 

Diols and derivatives. In the Combretastatins A family, the corresponding (E) stilbenes and bibenzyls, e.g. Combretastatin B-1 and analogues, which contain an -hybridized freely rotating ethane bridge, exhibit a decrease in antineoplastic activity when compared to the corresponding (Z)-stilbenes. To explore the possible conversion of the inactive ( )-isomer of Combretastatins A-1 and A-4 into a more active derivatives, a series of compounds was synthesized where the (E)-olefin unit was replaced by a freely rotating 5/73-hybridized chiral C-2 unit [35, 36]. 

Isoxazoline or isoxazole analogues represent an other series of Combretastatin A-4 analogues where the alkenyl motif of Combretastatin A-4 was replaced with an isoxazoline or isoxazole bearing the two aryl rings in positions 3,5. The synthetic strategy to this kind of compounds is exemplified in the following scheme [30]. 

For this reason, in the present section few lead, most active, compounds have been chosen for each class of derivatives or analogues, as divided in the previous sections their activities have been reported in comparison with that of a reference compound (usually Combretastatin A-4) to minimize the problems inherent to different experimental protocols for their determination. Fig. (19-21). 

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