Targeting DNA binding for NF-κB as an anticancer approach in hepatocellular carcinoma

Po Yee Chung, Pik Ling Lam, Yuan Yuan Zhou, Jessica Gasparello, Alessia Finotti, Adriana Chilin, Giovanni Marzaro, Roberto Gambari, Zhao Xiang 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

Research output: Journal article publicationJournal articleAcademic researchpeer-review

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number177
JournalCells
Volume7
Issue number10
DOIs
Publication statusPublished - 22 Oct 2018

Keywords

  • Anticancer
  • Hepatocellular carcinoma
  • NF-κB
  • Quinolines

ASJC Scopus subject areas

  • Medicine(all)

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