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

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

  • Eur J Med Chem. 2018 Jun 25:154:199-209. doi: 10.1016/j.ejmech.2018.05.025.
Yong Ling 1,  Qiu-Xing Yang 2,  Yu-Ning Teng 3,  Shi Chen 2,  Wei-Jie Gao 2,  Jing Guo 2,  Pei-Ling Hsu 4,  Yue Liu 2,  Susan L Morris-Natschke 4,  Chin-Chuan Hung 5,  Kuo-Hsiung Lee 6
Affiliations

Affiliations

  • 1 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, PR China; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States.
  • 2 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, PR China.
  • 3 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States; Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, 40402, Taiwan.
  • 4 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States.
  • 5 Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, 40402, Taiwan. Electronic address: cc0206hung@gmail.com.
  • 6 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, 40402, Taiwan. Electronic address: khlee@unc.edu.
PMID: 29803003 DOI: 10.1016/j.ejmech.2018.05.025
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).

Keywords

Amino-quinoline-5,8-dione; Antiproliferative activity; Apoptosis; Multidrug resistance; Quinone oxidoreductase 1 (NQO1); Reactive oxygen species (ROS).

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