Conformational mimetics of the α-methyl chalcone TUB091 binding tubulin: Design, synthesis and antiproliferative activity
| Autor: | Ernesto Quesada, Eva-María Priego, Sam Noppen, María-Jesús Pérez-Pérez, Oskía Bueno, Sandra Liekens, Juan Estévez-Gallego, María-José Camarasa, Gloria Tobajas, José-Fernando Díaz |
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| Přispěvatelé: | European Commission, Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2018 |
| Předmět: |
Chalcone
Molecular model Protein Conformation Stereochemistry Molecular modeling Antineoplastic Agents macromolecular substances Antiproliferative activity 010402 general chemistry 01 natural sciences Cell Line Tubulin binding chemistry.chemical_compound Chalcones Biomimetics Tubulin Neoplasms Drug Discovery Animals Humans Colchicine Benzodioxoles Cell Proliferation Pharmacology Binding Sites biology 010405 organic chemistry Chemistry Aryl Organic Chemistry Endothelial Cells General Medicine Tubulin Modulators 0104 chemical sciences Drug Design biology.protein Derivative (chemistry) Methyl group |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Based 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. This project has been supported by MINECO (SAF2012-39760- C02-01) and MINECO/FEDER (SAF2015-64629-C2-1-R), and to M.- J.P.-P., E.-M.P. E. Q. and M. J. C. and MINECO/FEDER BFU2016- 75319-R to J.F.D. The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery” (to M-J. P.-P. S.L. and J.-F.D.) We also would like to acknowledge Eef Meyen and Lizette Van Berckelaer for excellent technical assistance. |
| Databáze: | OpenAIRE |
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