Synthesis of New Quinolinequinone Derivatives and Preliminary Exploration of their Cytotoxic Properties

Abstract

A series of 7-amino- and 7-acetamidoquinoline-5,8-diones with aryl substituents at the 2-position were synthesized, characterized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The synthesis of lavendamycin analogs is illustrated. Metabolism studies demonstrated that 7-amino-analogues were generally better substrates for NQO1 than 7-amido-analogues as were compounds with smaller heteroaromatic substituents at the C-2 position. Surprisingly, only two compounds, 7-acetamido-2-(8’-quinolinyl)quinoline-5,8-dione (11) and 7-amino-2-(2-pyridinyl)quinoline-5,8-dione (23) showed selective cytotoxicity toward the NQO1-expressing MDA468-NQ16 breast cancer cells versus the NQO1-null MDA468-WT cells. For all other compounds, NQO1 protected against quinoline-5,8-dione cytotoxicity. Compound 22 showed a potent activity against human breast cancer cells expressing or not expressing NQO1 with IC50 values of respectively 190 nM and 140 nM and a low NQO1 mediated reduction rate, which suggests that the mode of action of 22 differs from lavendamycin and involves an unidentified target(s).

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

“…1). Moreover, small substituents such as amine groups at the C-6 or C-7 positions of the quinoline-5,8-dione moiety favorably impacted binding to the active site of NQO1 [16,17,24,25]. In this study, we coupled different alkyl-or aryl-amino fragments to the C6-or C7-position of quinoline-5,8-dione to design novel amino-quinoline-5,8-dione derivatives, and compared the cytotoxic effects of these compounds.…”

Quinoid systems in chemistry and pharmacology

“…Cytotoxicity was demonstrated to be closely related to molecular structure (Keyari et al, 2013). When a series of 7-amino and 7-acetamidoquinoline-5,8-diones with aryl substituents at the 2-position were evaluated as antitumor agents directed against NADPH/ubiquinone oxidoreductase, greater effectiveness was observed in amino (Fig.…”

Biological and In silico Evaluation of Quinolinedione and Naphthoquinone Derivatives as Potent Antibacterial Agents

“…The recent increase in microbial infection coupled with microbial resistance to available drugs has stimulated a dedicated interest in discovery of new antimicrobial agents. Quinolinequinone and its derivatives for over a century have been a focus of a large number of studies because of their wide spectrum of biological activities, which include potent antibacterial, antifungal antimalarial and antineoplastic properties. Mulchin and coworkers recently reported the anticancer, anti‐inflammatory and anti‐tuberculostatic activities of 6,7‐sustituted‐5,8‐quinolinequinone .…”