Latif, Ahmed DhahirJernei, TamasPodolski-Renic, AnaKuo, Ching-YingVagvolgyi, MateGirst, GaborZupko, IstvanDeveli, Elif SedefUlukaya, EnginWang, Hui-ChunPesic, MilicaCsampai, AntalHunyadi, Attila2020-08-302020-08-302020Latif, A. D., Jernei, T., Podolski-Renic, A., Kuo, C.-Y., Vagvolgyi, M., Girst, G., … Hunyadi, A. (2020). Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling. ANTIOXIDANTS, 9(6). https://doi.org/10.3390/antiox90605192076-3921https://doi.org/10.3390/antiox9060519https://hdl.handle.net/20.500.12713/394Hybrid 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 IC(50)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.eninfo:eu-repo/semantics/openAccessAntitumor Natural ProductProtoflavoneChalconeFerroceneHybrid CompoundFragment-Based Drug DesignDna Damage ResponseOxidative StressVirtual Combination StudyArticle9632545536WOS:0005512326000012-s2.0-85086673123Q110.3390/antiox9060519Q1