One-Pot Synthesis of Benzopyran-4-ones with Cancer Preventive and Therapeutic Potential


A one-pot synthesis of novel benzopyran-4-ones is described. In a tandem reaction, organobase-catalysed Michael addition of (RCOCH2COR2)-C-1 on chromone-3-carboxylic acid led to decarboxylation and pyran-4-one ring opening of the latter. This was followed by chromone- and/or chromanone ring closure of the resulting Michael adducts when R-1 is an ortho-hydroxyaryl group. Antioxidant testing of 14 derivatives identified strong antiradical properties of chromanones 3o-r (2.1-3.1 mu mol Trolox equiv./mu mol compound in the DPPH assay). Chromanones 3p and 3r and 2-styrylchromone 3k were also most potent in inducing the cytoprotective Keap1-Nrf2 signalling pathway in a reporter gene assay (fivefold induction at concentrations <3 mu M). Of the seven compounds evaluated for antiproliferative activities, 3k and 3r were the most active, inhibiting leukaemia K562 cell proliferation by 50% after 72 h at concentrations of 4.5 and 7.9 mu M, whereas normal peripheral blood mononuclear cells were not affected.






Talhi, O; Brodziak-Jarosz, L; Panning, J; Orlikova, B; Zwergel, C; Tzanova, T; Philippot, S; Pinto, DCGA; Paz, FAA; Gerhauser, C; Dick, TP; Jacob, C; Diederich, M; Bagrel, D; Kirsch, G; Silva, AMS

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The authors thank the Fundacao para a Ciencia e a Tecnologia (FCT), Portugal (grant numbers UID/QUI/00062/2013, UID/CTM/50011/2013) the European Union (EU), the Quadro de Referencia Estrategico Nacional (QREN), the Fundo Europeu de Desenvolvimento Regional (FEDER) and the Programa Operacional Factores de Competitividade (COMPETE) for funding the Organic Chemistry Research Unit, the Associate Laboratory Centro de Investigacao em Materiais Ceramicos e Compositos - CICECO and the Portuguese National NMR Network (RNRMN). European Community's Seventh Framework Programme (FP7/2007-20139, grant agreement number 215009) is also acknowledged for financial support. The General Directorate for Scientific Research and Technological Development-DGRSDT of Algeria is thanked for financial support. The authors further wish to thank FCT for specific funding toward the purchase of the single-crystal X-ray diffractometer. O. T. appreciates support for his post-doctoral position through the project New Strategies Applied to Neuropathological Disorders (CENTRO-07-ST24-FEDER-002034), co-funded by QREN, Mais Centro-Programa Operacional Regional do Centro and the EU, FEDER. B. O. thanks RSL, Luxembourg, for her post-doctoral grant. Thanks are also due to the Fondation de Recherche Cancer et Sang, the Recherches Scientifiques Luxembourg association, the Een Haerz fur Kriibskrank Kanner association, the Action Lions Vaincre le Cancer association, Interreg IVA project Corena, and the Televie Luxembourg for funding LBMCC. M. D. and B. O. also thank the Research Institute of Pharmaceutical Sciences by the NRF of the MEST of Korea for the Tumor Microenvironment GCRC 2012-0001184 grant and by the Brain Korea (BK21) PLUS program for funding. The AREc32 cell line used in this study was kindly provided by Professor Roland Wolf (University of Dundee, UK) and the Cancer Research UK.

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