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Título

Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach

AutorCanela, 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 publicación2014
EditorAmerican Chemical Society
CitaciónJournal of Medicinal Chemistry 57: 3924- 3938 (2014)
ResumenVascular 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.
URIhttp://hdl.handle.net/10261/98408
DOI10.1021/jm401939g
Identificadoresdoi: 10.1021/jm401939g
issn: 0022-2623
e-issn: 1520-4804
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