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

摘要: 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 design antitumor hybrid based on inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, pro-oxidant ferrocene or chalcone fragment. Four new triazole-coupled hybrids were prepared. The cytotoxic against human breast cancer cell lines in vitro, showing IC50 values the sub-micromolar range. nature interactions between relevant was evaluated by Chou-Talalay method. Experimental combination treatment showed additive effects slight/moderate synergism, while strong synergism observed when virtually combined into their hybrids, suggesting benefit coupling. All inhibitors ATR-mediated activation Chk1, they interfered redox balance cells leading mitochondrial membrane depolarization. Additionally, induced late apoptosis primary necrosis MDA-MB-231 MCF-7 cells, respectively. Our results demonstrate that coupling ATR-dependent signaling protoflavone dramatically increases activity compared either fragment alone. Such may offer attractive novel various cancers.