Combretastatin rings

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. 

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 tri-methoxylation pattern of ring A in natural combretastatins (probably coming from the shikimate biosynthetic patway) is generally considered critical for efficient binding to tubulin, albeit some doubts have been reported [6]. Also a recent work on Fluorcombstatin shed some shadow on this point [7]. 

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... 

Among the modifications of ring A, fluorcombstatin and related 3-halostilbenes have been recently reported [7, 14]. The fluoro, chloro, and bromo halocombstatins were nearly equivalent to Combretastatin A-4 as inhibitors of tubulin polymerization and of the binding of colchicine to tubulin and retained the powerful human cancer cell line inhibitory activity of combretastatin A-4. 

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. 

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]. 

Isoxazoline or isoxazole analogues represent an other series of Combretastatin A-4 analogues where the alkenyl motif of Combretastatin A-4 was replaced by a five-membered heterocycle (isoxazoline or isoxazole). The synthetic strategy to isoxazolines or isoxazoles bearing two aromatic rings on position 4,5 is reported in the Scheme 9 [30]. 

The spatial relationship between the two aromatic rings of Combretastatin A-4, colchicine and similar drugs is an important... 

Among the 6-membered heterocombretastatins, where the B ring was replaced by a variety of 6-membered heterocycles (pyridines, pyrimidines, pyridazines, pyrazines, pyridinium salts) the pyridone derivative 14 showed strong antimitotic activity IC50 2 jiiM, the same value of Combretastatin A-4) and cytotoxicity IC50 19.2 nM, versus 8.7 nM of Combretastatin A-4), along with excellent water-solubility. 

The pyrazole- and thiazole analogues of the 3 -deoxy-3 -amino-4 -methoxy Combretastatin A-4 showed potent antimitotic (IC50 3.0 pM and IC50 10 pM) activity. The former showed also a potent cytotoxic activity (IC50 8.4 nM ). Moderate antimitotic activity (IC50 3.0 pM) and weak cytotoxic activity was observed for a triazole derivative, whereas tetrazole ring confers potent antimitotic (ICso 2.0 pM) as well as cytotoxic activity. Compounds with potent cjdotoxicity were further evaluated in vivo in the Colon murine tumor model. The best antitumor activity in vivo, expressed as tumour growth suppression, was observed for the thiazole and tetrazole derivatives with values comparable to the ones observed for 3 -deoxy-3 -amino Combretastatin A-4 hydrochloride. 

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