Interaction of 4-arylcoumarin analogues of combretastatins with microtubule network of HBL100 cells and binding to tubulin
| Autor: | Catherine Grégoire, Sebastien Combes, Robert Gilli, Vincent Peyrot, Véronique Bourgarel-Rey, Jean-Pierre Finet, Manon Carré, Pascale Barbier, Catherine Rappl |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Apoptosis Biology Calorimetry Biochemistry Microtubules Tubulin binding chemistry.chemical_compound Structure-Activity Relationship Microtubule Coumarins Tubulin Cell Line Tumor Stilbenes Humans Mitosis Microtubule nucleation Combretastatin Cell Cycle Biological activity Antineoplastic Agents Phytogenic Spectrometry Fluorescence chemistry biology.protein Thermodynamics Pharmacophore Protein Binding |
| Zdroj: | Biochemistry. 45(30) |
| ISSN: | 0006-2960 5437-5444 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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