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Conformational mimetics of the α-methyl chalcone TUB091 binding tubulin: Design, synthesis and antiproliferative activity

AuthorsBueno, Oskía; Tobajas, Gloria; Quesada, Ernesto; Estévez-Gallego, Juan; Noppen, Sam; Camarasa Rius, María José ; Díaz, José Fernando ; Liekens, Sandra; Priego, Eva María ; Peréz-Pérez, María-Jesús
Antiproliferative activity
Molecular modeling
Issue Date2018
CitationEuropean Journal of Medicinal Chemistry 148: 337-348 (2018)
AbstractBased on the conformation of the α-methyl chalcone TUB091 in its complex with tubulin, a series of conformational mimetics have been designed and synthesized where the methyl group of the chalcone has been fused to phenyl ring B resulting in 1,2,3,4-tetrahydronaphthalen-2-yl aryl ketones. Among the synthesized compounds, the 5-amino-6-methoxy derivative, with a similar substitution pattern to that of TUB091, showed antiproliferative activity around 20 nM against tumor and endothelial cells. Tubulin binding experiments confirmed its binding to tubulin at the colchicine site with a Kb of 2.4 × 10 M resulting in the inhibition of the in vitro assembly of purified tubulin. Moreover, based on the recently reported complex of combretastatin A4 (CA4) with tubulin, a comparative analysis of the binding mode of CA4 and the α-methyl chalcone to tubulin has been performed.
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2018.02.019
Identifiersdoi: 10.1016/j.ejmech.2018.02.019
issn: 0223-5234
e-issn: 1768-3254
Appears in Collections:(CIB) Artículos
(IQM) Artículos
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