title: 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 analogues 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 potent activity against human breast cancer cells expressing or not expressing NQO1, with respective IC50 values of 190 nM and 140 nM and a low NQO1-mediated reduction rate, which suggests that the mode of action of 22 differs from that of lavendamycin and involves an unidentified target(s).
authors.affiliation: Core Laboratory for Neuromolecular Production, Department of Biomedical and Pharmaceutical Sciences, The University of Montana , Missoula, Montana 59812, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Keyari
authors.forename: Alison K
authors.initials: AK
authors.lastname: Kearns
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Duncan
authors.forename: Emily A
authors.initials: EA
authors.lastname: Eickholt
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Abbott
authors.forename: Howard D
authors.initials: HD
authors.lastname: Beall
authors.forename: Philippe
authors.initials: P
authors.lastname: Diaz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004563:Electrochemistry; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008872:Microwaves; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D010101:Oxygen Consumption / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000970:Antineoplastic Agents; D004396:Coloring Agents; D007202:Indicators and Reagents; D011804:Quinolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D045304:Cytochromes c; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C022616:thiazolyl blue