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Title: Synthesis and biological evaluation of alpha-bromoacryloylamido indolyl pyridinyl propenones as potent apoptotic inducers in human leukaemia cells
Authors: Romagnoli, Romeo
Prencipe, Filippo
Lopez-Cara, Luisa Carlota
Oliva, Paola
Baraldi, Stefania
Baraldi, Pier Giovanni
Estévez-Sarmiento, Francisco 
Quintana, Jose 
Estévez, Francisco 
UNESCO Clasification: 32 Ciencias médicas
Keywords: Apoptosis
Indole-based chalcone
α-bromoacryloyl moiety
In vitro antiproliferative activity
Issue Date: 2018
Journal: Journal of Enzyme Inhibition and Medicinal Chemistry 
Abstract: The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. To investigate the influence of the position of the pyridine nitrogen on biological activity, two different series of α-bromoacryloylamido indolyl pyridinyl propenones 3a–h and 4a–d were designed and synthesized by a pharmacophore hybridization approach and evaluated for their antiproliferative activity against a panel of six human cancer cell lines. These hybrid molecules were prepared to combine the α-bromoacryloyl moiety with two series of indole-inspired chalcone analogues, possessing an indole derivative and a 3- or 4-pyridine ring, respectively, linked on either side of 2-propen-1-one system. The structure-activity relationship was also investigated by the insertion of alkyl or benzyl moieties at the N-1 position of the indole nucleus. We found that most of the newly synthesized displayed high antiproliferative activity against U-937, MOLT-3, K-562, and NALM-6 leukaemia cell lines, with one-digit to double-digit nanomolar IC50values. The antiproliferative activities of 3-pyridinyl derivatives 3f–h revealed that N-benzyl indole analogues generally exhibited lower activity compared to N-H or N-alkyl derivatives 3a–b and 3c–e, respectively. Moreover, cellular mechanism studies elucidated that compound 4a induced apoptosis along with a decrease of mitochondrial membrane potential and activated caspase-3 in a concentration-dependent manner.
ISSN: 1475-6366
DOI: 10.1080/14756366.2018.1450749
Source: Journal of Enzyme Inhibition and Medicinal Chemistry[ISSN 1475-6366],v. 33, p. 727-742
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