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Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets
Open AccessBrief Report

Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma

State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy
Clinical Division, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
Griffith Medical School, Griffith University, Gold Coast, QLD 4222, Australia
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
School of Optometry, The Hong Kong Polytechnic University, Hong Kong, China
Authors to whom correspondence should be addressed.
Cells 2018, 7(10), 177;
Received: 20 September 2018 / Revised: 18 October 2018 / Accepted: 19 October 2018 / Published: 22 October 2018
(This article belongs to the Section Cell Signaling and Regulated Cell Death)
Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma. View Full-Text
Keywords: NF-κB; anticancer; hepatocellular carcinoma; quinolines NF-κB; anticancer; hepatocellular carcinoma; quinolines
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Chung, P.Y.; Lam, P.L.; Zhou, Y.; Gasparello, J.; Finotti, A.; Chilin, A.; Marzaro, G.; Gambari, R.; Bian, Z.; Kwok, W.M.; Wong, W.Y.; Wang, X.; Lam, A.K.-Y.; Chan, A.S.-C.; Li, X.; Ma, J.Y.W.; Chui, C.H.; Lam, K.H.; Tang, J.C.O. Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma. Cells 2018, 7, 177.

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