Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma
Po Yee Chung,
Pik Ling Lam,
Yuanyuan Zhou,
Jessica Gasparello,
Alessia Finotti,
Adriana Chilin,
Giovanni Marzaro,
Roberto Gambari,
Zhaoxiang Bian,
Wai Ming Kwok,
Wai Yeung Wong,
Xi Wang,
Alfred King-yin Lam,
Albert Sun-chi Chan,
Xingshu Li,
Jessica Yuen Wuen Ma,
Chung Hin Chui,
Kim Hung Lam,
Johnny Cheuk On Tang
Affiliations
Po Yee Chung
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Pik Ling Lam
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Yuanyuan Zhou
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Jessica Gasparello
Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
Alessia Finotti
Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
Adriana Chilin
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy
Giovanni Marzaro
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy
Roberto Gambari
Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
Zhaoxiang Bian
Clinical Division, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
Wai Ming Kwok
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Wai Yeung Wong
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Xi Wang
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Alfred King-yin Lam
Griffith Medical School, Griffith University, Gold Coast, QLD 4222, Australia
Albert Sun-chi Chan
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
Xingshu Li
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
Jessica Yuen Wuen Ma
School of Optometry, The Hong Kong Polytechnic University, Hong Kong, China
Chung Hin Chui
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Kim Hung Lam
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Johnny Cheuk On Tang
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
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.
