Interaction of 4-arylcoumarin analogues of combretastatins with microtubule network of HBL100 cells and binding to tubulin |
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Authors: | Rappl Catherine Barbier Pascale Bourgarel-Rey Véronique Grégoire Catherine Gilli Robert Carre Manon Combes Sébastien Finet Jean-Pierre Peyrot Vincent |
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Affiliation: | FRE-CNRS 2737, Universités Aix-Marseille 1 et 2, Cytosquelette et Intégration des Signaux du Micro-Environnement Tumoral, 27 boulevard Jean Moulin, 13385 Marseille Cedex 5, France. |
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Abstract: | The synthesis of different 4-arylcoumarin analogues of combretastatin A-4 led to the identification of two new compounds (1 and 2) with potent cytotoxic activity on a CEM leukemia cell line and a third one completely inactive (compound 3). It was suggested that the cytotoxicity of compounds 1 and 2 may be related to their interaction with microtubules and tubulin, since these compounds inhibit microtubule formation from purified tubulin in vitro [Bailly et al. (2003) J. Med. Chem. 46 (25), 5437-5444]. In the present study, tubulin was identified as the main target of these molecules. We studied structure-activity relationships of these compounds using biological experiments specific for tubulin binding. The modification of cell cycle progression induced by compounds 1 and 2 was characterized by an apoptotic induction on human breast cells (HBL100). In addition, these two molecules disturbed cell survival by depolymerizing the microtubule network, leading to a mitotic block. We then determined the thermodynamic parameters of their interaction with purified tubulin by fluorescence spectroscopy and isothermal microcalorimetry. These results, together with a superimposition of the molecule on colchicine in the X-ray-determined three-dimensional structure model of tubulin-colchicine complex, allowed us to identify the pharmacophore of the combretastatin A-4 analogues responsible for their biological activity. |
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