Development of novel amino-quinoline-5,8-dione derivatives as NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors with potent antiproliferative activities.

Abstract

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).

• Authors: Yong Ling, Qiu-Xing Yang, Yu-Ning Teng, Shi Chen, Wei-Jie Gao, Jing Guo, Pei-Ling Hsu, Yue Liu, Susan L Morris-Natschke, Chin-Chuan Hung, Kuo-Hsiung Lee
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 154 Pg. 199-209 (Jun 25 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29803003 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Quinolones
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Molecular Structure
• NAD(P)H Dehydrogenase (Quinone) (antagonists & inhibitors, metabolism)
• Quinolones (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship