Tubulin binders

There are a number of reviews published in the field of tubulin binders as anti-cancer agents, but these mostly focus on the cytotoxicity of combre-tastatins and chalcones [1,40,41], There has also been much published on... 

Moustafa and Ahmed reported the synthesis of isoxazoles [92,93]. These compounds are related to pyrazoles except that an oxygen replaces the amine nitrogen. Scheme 49 shows the synthesis of 182 from the corresponding chal-cone 183 by reaction with hydroxylamine. Although these compounds were not tested for cytotoxicity as tubulin binders, they were found to possess antibacterial and anti-fungal activity. 

Although none of the pyrazolines have been tested as tubulin binders Jeong et al. reported the activity of pyrazolines for their lipid peroxidation inhibitory... 

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. 

Tubulin binders are usually large and complex natural products. The difficulties and challenges encountered in the chemical synthesis of these molecules and then-derivatives, with the goal of building solid structure-activity relationship (SAR) datasets, are described in the first and second chapters of the book. 

Even though near-atomic resolution structures are available only for a few tubulin binders, these structures are very valuable as their represent the basis for a number of studies aimed at discovering the binding modes of other MT-targeting drugs. 

Since the discovery of the therapeutic potential of tubulin targeting drugs, there has been a demand for structural information at the molecular level about the binding pose of the small-molecule ligands, very much needed by the medicinal chemists for the rational design of novel derivatives. Even nowadays, near-atomic resolution structures are available only for a few tubulin binders, namely, the EC-derived structures of the MT-stabilizers PTX [11] and EpoA [26], and the X-ray structures of complexes of tubulin/RB3-SLD with the MT-destabilizers colchicine [12] and vinblastine [13]. 

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. 

T-138067 / Batabulin (18) Phase III (liver cancer) 11-165 nM Tularik Inc. Irreversible P-tubulin binder [59]... 

Several additional compounds derived from S. ceUulosum species are currently under study for pharmaceutical development (see Figure 12.6) Chlorotoiul was recently shown to exhibit impressive antimalarial activity in mouse models [83] and the tubulin binder disorazole has demonstrated imposing activity in cancer models in mice when administered as peptide conjugate targeting... 

Antimitotics Cytotoxic agents Tubulin binders Cells... 

Vinblastine (4) and vincristine (5) are closely related indole-dihydroindole dimers (bisindole alkaloids), isolated from Catharanthus roseus (L.) G. Don (formerly known as Vinca rosea L.), the Madagascar periwinkle. Both of these anticancer agents, known as vinca alkaloids in the medical literature, are specific binders of tubulin, leading to tubulin depolymerization and cell cycle arrest in the metaphase stage. 

Caceres A, Binder LI, Payne MR, Bender P, Rebhun L, Steward O (1984) Differential subcellular localization of tubulin and the microtubule-associated protein MAP2 in brain tissue as revealed by immunocytochemistry with monoclonal hybridoma antibodies. J Neurosci 4 394-410. 

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