Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling
2020
Аутори:
Latif, Ahmed DhahirJernei, Tamás
Podolski-Renić, Ana
Kuo, Ching-Ying
Vágvölgyi, Máté
Girst, Gábor
Zupkó, István
Develi, Sedef
Ulukaya, Engin
Wang, Hui-Chun
Pešić, Milica
Csámpai, Antal
Hunyadi, Attila
Тип документа:
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт:
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.
Кључне речи:
Antitumor natural product; Chalcone; DNA damage response; Ferrocene; Fragment-based drug design; Hybrid compound; Oxidative stress; Protoflavone; Virtual combination studyИзвор:
Antioxidants, 2020, 9, 6, 519-Финансирање / пројекти:
- National Research, Development and Innovation Office, Hungary (NKFIH; K-119770 and K-129037)
- Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT
DOI: 10.3390/antiox9060519
ISSN: 2076-3921
PubMed: 32545536