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Title

Targeting the colchicine site in tubulin through cyclohexanedione derivatives

AuthorsCanela, María-Dolores ; Bueno, O.; Noppen, Sam; Sáez-Calvo, Gonzalo; Estévez Gallego, J.; Díaz, José Fernando ; Camarasa Rius, María José ; Liekens, Sandra; Peréz-Pérez, María-Jesús ; Priego, Eva María
Issue Date2016
PublisherRoyal Society of Chemistry (UK)
CitationRSC Advances 6: 19492-19506 (2016)
AbstractCyclohexanedione derivatives represent a new family of colchicine-site binders that were identified through a ligand-based virtual screening approach. Structural modifications have now been performed at both distal sites of our identified hit [2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (4)] in order to improve tubulin binding affinity, anti-proliferative activity and/or aqueous solubility. The results obtained indicate that the 2-methoxyphenyl ring, the fragment located closer to the αβ-tubulin interface according to docking studies, is the one that allows structural variation in order to improve the K value against tubulin (as in compound 20a with a K = 1.3 × 10 M, analogous to colchicine) or to improve aqueous solubility, as in compound 22c, being more than 10 times more soluble than the previous hit 4.
Publisher version (URL)http://dx.doi.org/10.1039/c5ra26807a
URIhttp://hdl.handle.net/10261/134327
DOI10.1039/c5ra26807a
Identifiersdoi: 10.1039/c5ra26807a
issn: 2046-2069
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