Development of novel amino-quinoline-5,8-dione derivatives as NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors with potent antiproliferative activities
| Autor: | Pei Ling Hsu, Shi Chen, Yong Ling, Kuo Hsiung Lee, Susan L. Morris-Natschke, Yu Ning Teng, Liu Yue, Chin-Chuan Hung, Qiu Xing Yang, Wei Jie Gao, Jing Guo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Antineoplastic Agents Quinolones Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Cell Line Tumor Drug Discovery NAD(P)H Dehydrogenase (Quinone) Humans Enzyme Inhibitors Cytotoxicity Cell Proliferation Pharmacology Dose-Response Relationship Drug Molecular Structure Chemistry Liver cell Organic Chemistry Quinoline General Medicine Multiple drug resistance 030104 developmental biology Biochemistry Cell culture Apoptosis 030220 oncology & carcinogenesis Cancer cell NAD+ kinase Drug Screening Assays Antitumor |
| Zdroj: | European journal of medicinal chemistry. 154 |
| ISSN: | 1768-3254 |
| Popis: | Fourteen novel amino-quinoline-5,8-dione derivatives (6a-h and 7a-h) were designed and synthesized by coupling different alkyl- or aryl-amino fragments at the C6- or C7-position of quinoline-5,8-dione. All target compounds showed antiproliferative potency in the low micromolar range in both drug sensitive HeLaS3 and multidrug resistant KB-vin cell lines. Compounds 6h, 6d, 7a, and 7d exhibited more potent antiproliferative effects than the other compounds. Especially, compounds 6d and 7d displayed NQO1-dependent cytotoxicity and competitive NQO1 inhibitory effects in both drug sensitive HeLaS3 and multidrug resistant KB-vin cell lines. Furthermore, compounds 6h, 6d, 7a, and 7d induced a dose-dependent lethal mitochondrial dysfunction in both drug sensitive HeLaS3 and multidrug resistant KB-vin cells by increasing intracellular reactive oxygen species (ROS) levels. Notably, compound 7d selectively inhibited cancer cells, but not non-tumor liver cell proliferation in vitro, and significantly triggered HeLaS3 cell apoptosis by regulating apoptotic proteins of Bcl-2, Bax, and cleaved caspase-3 in a dose-dependent manner. Our findings suggest that these novel C6- or C7-substituted amino-quinoline-5,8-dione derivatives, such as 7d, could be further developed in the future as potent and selective antitumor agents to potentially circumvent multi-drug resistance (MDR). |
| Databáze: | OpenAIRE |
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