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Título: | Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach |
Autor: | Canela, María-Dolores CSIC; Peréz-Pérez, María-Jesús CSIC ORCID ; Noppen, Sam; Sáez-Calvo, Gonzalo CSIC; Díaz, José Fernando CSIC ORCID ; Camarasa Rius, María José CSIC ORCID; Liekens, Sandra; Priego, Eva María CSIC ORCID | Fecha de publicación: | 2014 | Editor: | American Chemical Society | Citación: | Journal of Medicinal Chemistry 57: 3924- 3938 (2014) | Resumen: | Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the α,β-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl) amino)ethylidene)-5-phenylcyclohexane-1,3-dione (compound 16c) with an IC 50 = 0.09 ± 0.01 μM in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with N,N′-ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 μM and inhibited the migration and invasion of human breast carcinoma cells at 0.4 μM. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties. | URI: | http://hdl.handle.net/10261/98408 | DOI: | 10.1021/jm401939g | Identificadores: | doi: 10.1021/jm401939g issn: 0022-2623 e-issn: 1520-4804 |
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Canela-et-al_2014_JMedChem_57.pdf | 1,46 MB | Adobe PDF | Visualizar/Abrir | |
Canela-et-al_2014_JMedChem_57_Support-Info.pdf | 294,77 kB | Adobe PDF | Visualizar/Abrir |
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