期刊
SCIENTIFIC REPORTS
卷 8, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41598-018-22382-x
关键词
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资金
- Spanish Ministerio de Economia y Competitividad [SAF2015-64629-C2-1-R, SAF2015-64629-C2-2]
- Swiss National Science Foundation [31003A_166608]
- COST action [CM1407]
- AEI/FEDER, UE [BFU2016-75319-R]
- SEQT
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 G(2)/M phase and induced apoptosis at sub mu M 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.
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