17844-66-5Relevant articles and documents
Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach
Canela, María-Dolores,Pérez-Pérez, María-Jesús,Noppen, Sam,Sáez-Calvo, Gonzalo,Díaz, J. Fernando,Camarasa, María-José,Liekens, Sandra,Priego, Eva-María
supporting information, p. 3924 - 3938 (2014/06/09)
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.
SUBSTITUTED DIHYDROPYRIDINES AND METHODS OF USE
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Page/Page column 69-70, (2010/11/27)
Compounds are provided that are modulators of the C5a receptor. The compounds are substituted dihydropyridines and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activtation of C5a receptors.
