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Publication Abstract from PubMed

Microtubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the high-resolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC50 values in the nM range, arrested cell cycle progression at the G2/M phase and induced apoptosis at sub muM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a K b value of 2.87 x 10(8) M(-1) which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand.

High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design.,Bueno O, Estevez Gallego J, Martins S, Prota AE, Gago F, Gomez-SanJuan A, Camarasa MJ, Barasoain I, Steinmetz MO, Diaz JF, Perez-Perez MJ, Liekens S, Priego EM Sci Rep. 2018 Mar 9;8(1):4242. doi: 10.1038/s41598-018-22382-x. PMID:29523799^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.