Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 167, Issue -, Pages 61-75Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.01.066
Keywords
1,3,5-Substituted indole derivatives; Kinase multi-target inhibitor; Target fishing; In cell studies
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Funding
- Regional Council of Campania Region
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A series of 1,3,5-substituted indole derivatives was prepared to explore the anti-proliferative activity against a panel of human tumour cell lines. A 5-carboxamide derivative (27) emerged as the most potent compound of this series, inhibiting the HeLa cell growth at sub-micromolar concentrations. Target fishing of 27 using a combination of inverse virtual screening (IVS) approach and ligand-based shape similarity study identified the top-ranked targets for 27 as belonging to kinome. These results were further confirmed by in vitro binding assays, leading to the identification of 27 as multi-target kinase inhibitor. The compound 27 was further characterized for its antiproliferative activity by in cell studies, showing a mechanism of action involving modification of the cell cycle, increase in ROS release and caspase 3-expression and decrease in ERK expression. (C) 2019 Elsevier Masson SAS. All rights reserved.
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