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Molecules 2019, 24(1), 129; https://doi.org/10.3390/molecules24010129

New Alkoxy Flavone Derivatives Targeting Caspases: Synthesis and Antitumor Activity Evaluation

1
Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
2
Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal
3
CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal
4
LAQV/REQUIMTE, Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 4 December 2018 / Revised: 23 December 2018 / Accepted: 25 December 2018 / Published: 31 December 2018
Full-Text   |   PDF [3216 KB, uploaded 31 December 2018]   |  

Abstract

The antitumor activity of natural flavonoids has been exhaustively reported. Previously it has been demonstrated that prenylation of flavonoids allows the discovery of new compounds with improved antitumor activity through the activation of caspase-7 activity. The synthesis of twenty-five flavonoids (428) with one or more alkyl side chains was carried out. The synthetic approach was based on the reaction with alkyl halide in alkaline medium by microwave (MW) irradiation. The in vitro cell growth inhibitory activity of synthesized compounds was investigated in three human tumor cell lines. Among the tested compounds, derivatives 6, 7, 9, 11, 13, 15, 17, and 18 revealed potent growth inhibitory activity (GI50 < 10 μM), being the growth inhibitory effect of compound 13 related with a pronounced caspase-7 activation on MCF-7 breast cancer cells and yeasts expressing human caspase-7. A quantitative structure-activity relationship (QSAR) model predicted that hydrophilicity, pattern of ring substitution/shape, and presence of partial negative charged atoms were the descriptors implied in the growth inhibitory effect of synthesized compounds. Docking studies on procaspase-7 allowed predicting the binding of compound 13 to the allosteric site of procaspase-7. View Full-Text
Keywords: flavonoids; O-heterocycles; alkylation; antitumor activity; apoptosis; caspase activators flavonoids; O-heterocycles; alkylation; antitumor activity; apoptosis; caspase activators
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Moreira, J.; Ribeiro, D.; Silva, P.M.A.; Nazareth, N.; Monteiro, M.; Palmeira, A.; Saraiva, L.; Pinto, M.; Bousbaa, H.; Cidade, H. New Alkoxy Flavone Derivatives Targeting Caspases: Synthesis and Antitumor Activity Evaluation. Molecules 2019, 24, 129.

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