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Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling

1
Institute of Pharmacodynamics and Biopharmacy, Interdisciplinary Excellence Centre, University of Szeged, Eötvös str. 6, H-6720 Szeged, Hungary
2
Institute of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Eötvös str. 6, H-6720 Szeged, Hungary
3
Institute of Chemistry, Eötvös Loránd University, P.O. Box 32, H-1518 Budapest-112, Hungary
4
Department of Neurobiology, Institute for Biological Research “Siniša Stanković”- National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
5
Graduate Institute of Natural Products, Kaohsiung Medical University, Shih-Chuan 1st Rd. 100, Kaohsiung 807, Taiwan
6
Interdisciplinary Centre for Natural Products, University of Szeged, Eötvös str. 6, H-6720 Szeged, Hungary
7
Molecular Cancer Research Center, Istinye University, 34010 Topkapi, Istanbul, Turkey
*
Authors to whom correspondence should be addressed.
On leave from Department of Pharmacology and Toxicology, Faculty of Medicine, Wasit University, Wasit 52001, Iraq.
Equal contribution from the first two authors.
Antioxidants 2020, 9(6), 519; https://doi.org/10.3390/antiox9060519
Received: 7 May 2020 / Revised: 4 June 2020 / Accepted: 8 June 2020 / Published: 12 June 2020
Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, and a pro-oxidant ferrocene or chalcone fragment. Four new triazole-coupled hybrids were prepared. The compounds were cytotoxic against human breast cancer cell lines in vitro, showing IC50 values in the sub-micromolar range. The nature of interactions between relevant fragments of the hybrids was evaluated by the Chou–Talalay method. Experimental combination treatment with the fragments showed additive effects or slight/moderate synergism, while strong synergism was observed when the fragments were virtually combined into their hybrids, suggesting a relevant pharmacological benefit of the coupling. All hybrids were strong inhibitors of the ATR-mediated activation of Chk1, and they interfered with the redox balance of the cells leading to mitochondrial membrane depolarization. Additionally, they induced late apoptosis and primary necrosis in MDA-MB-231 and MCF-7 breast cancer cells, respectively. Our results demonstrate that coupling the ATR-dependent signaling inhibitor protoflavone with a pro-oxidant chalcone dramatically increases the antitumor activity compared with either fragment alone. Such compounds may offer an attractive novel strategy for the treatment of various cancers. View Full-Text
Keywords: antitumor natural product; protoflavone; chalcone; ferrocene; hybrid compound; fragment-based drug design; DNA damage response; oxidative stress; virtual combination study antitumor natural product; protoflavone; chalcone; ferrocene; hybrid compound; fragment-based drug design; DNA damage response; oxidative stress; virtual combination study
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Latif, A.D.; Jernei, T.; Podolski-Renić, A.; Kuo, C.-Y.; Vágvölgyi, M.; Girst, G.; Zupkó, I.; Develi, S.; Ulukaya, E.; Wang, H.-C.; Pešić, M.; Csámpai, A.; Hunyadi, A. Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling. Antioxidants 2020, 9, 519.

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