Combretastatin derivative

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. 

Methoxy indole-containing combretastatin derivatives, (I), and prodrugs, (II), prepared by Pinney (2) were found effective as antimitotic and antitubulin polymerization agents and used in the selective destruction of tumor cell vasculature. 

Also 1,2,3-triazole derivatives, evaluated against the growth of murine B16 melanoma cells, exhibited a cytotoxicity comparable to the cis-combretastatins, with the IC50 values for compounds 3,4,5-trimethoxy-substituted 1,2,3-triazole and cw-combretastatin derivatives as 56 Mand 55 nM, respectively. 

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. 

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. 

Pettit (3) prepared water-soluble, trans-isomer derivatives, (III), of combretastatin A-4, which were used in the treatment of neoplastic diseases. 

Pettit (6) prepared phenstatin, (VII), and prodrug derivatives, (VIII), which were more effective tubulin polymerization inhibitors than colchicine and more effective as tubulin binder inhibitors than combretastatin. 

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. 

Combretastatin B-1 and derivatives are generally obtained by idrogenation of Z/E mixtures of the corresponding stilbenes [8]. 

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... 

Other derivatives were synthesized where the 3 substituent was in turn an halide [14], a nitrogen quaternary salt-containing side chains [15], an O-alkylamine [15], a nitro group [15], an azido group [16], a functionalized C-2 unit [17]. Several fluorinated analogues of Combretastatins A-1 and A-4 were synthesized and their in vitro anticancer properties determined. The most active fluoro analogue 3 -deoxy-3 -fluoro-combretastatin A-4 retains the potent cell growth inhibitory properties of Combretastatin A-4 [14]. 

More recently a series of derivatives with nitro or serinamide substituents at the 2 5 or 6 position of Combretastatin A-4 were synthesized via a typical Wittig reaction. Some of them are strong inhibitors of tubulin assembly and vascular disrupting agents [21]. 

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. 

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]. 

Dihydroxylation of the stilbene double bond in the trans isomers of Combretastatin A-1 and A-4 produced diols which by treatment with boron trifluoride in ethyl ether [44] or with trifluoroacetic acid [17] resulted in pinacolic rearrangement to produce an aldehyde. The aldehyde was converted in a variety of derivatives, as illustrated in the Scheme 20, via the following reaction sequence reduction with sodium borohydride to primary alcohol which was derivatized to the corresponding mesylate or tosylate, substitution with sodium azide and final reduction to amine with lithium aluminum hydride. Alternatively the aldehyde was converted to oxime which was catalitically hydrogenated to amine [17]. 

When the former protocol was applied to Combretastatin A-1, attempted conversion of the mesylate to azide failed and took an other course, affording a tetraidro-benzofuran derivative, most likely arising from nucleophilic attack of a deprotected 2 hydroxyl on the mesylate [17]. Preliminary biological tests, still in course, showed a potential antitubulin activity of the benzotetraidrofuran derivative. 

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