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Title: Design, synthesis and antiproliferative activity of novel heterobivalent hybrids based on imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole scaffolds
Authors: Romagnoli, Romeo
Baraldi, Pier Giovanni
Prencipe, Filippo
Balzarini, Jan
Liekens, Sandra
Estévez, Francisco 
Keywords: Alpha-Halogenoacrylic Derivatives
Programmed Cell-Death
Human Leukemia-Cells
Apoptosis, et al
Issue Date: 2015
Publisher: 0223-5234
Journal: European Journal of Medicinal Chemistry 
Abstract: Heterobivalent ligands constituted by two different pharmacophores that bind to different molecular targets or to two distinct sites on the same molecular target could be one of the methods used for the treatment of cancer. In view of the importance of imidazo[1,2-6][1,3]thiazole and imidazo[1,2-b][1,3,4] thiadiazole as privileged structures for the preparation of novel anticancer agents, we decided to explore the synthesis and biological evaluation of molecular conjugates comprising these fused bicyclic systems tethered at their C-6 position by a meta-(alpha-bromoacryloylamido)phenyl moiety. We found that most of the hybrid compounds displayed high antiproliferative activity toward a wide panel of cancer cell lines, with one-digit micromolar to submicromolar 50% inhibitory concentrations (IC50). We have observed that selected compounds 7d, 7e, 7n and 8c induced apoptosis, which was associated with the release of cytochrome c and cleavage of multiple caspases. Overexpression of the protective mitochondrial protein Bcl-2 did not confer protection to cell death induced by these compounds. (C) 2015 Elsevier Masson SAS. All rights reserved.
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2015.06.042
Source: European Journal of Medicinal Chemistry[ISSN 0223-5234],v. 101, p. 205-217
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