Synthesis of New Quinolinequinone Derivatives and Preliminary Exploration of their Cytotoxic Properties
| Autor: | Charles M. Keyari, Emily A. Eickholt, Nathan S. Duncan, Philippe Diaz, Alison K. Kearns, Howard D. Beall, Geoffrey Abbott |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Stereochemistry Cell Survival Tetrazolium Salts Antineoplastic Agents Article chemistry.chemical_compound Structure-Activity Relationship Oxygen Consumption Cell Line Tumor Drug Discovery Electrochemistry NAD(P)H Dehydrogenase (Quinone) Cytotoxic T cell Structure–activity relationship Humans Lavendamycin Cytotoxicity Coloring Agents Microwaves Chemistry Aryl Cytochromes c Thiazoles Cancer cell Quinolines Molecular Medicine Indicators and Reagents NAD+ kinase Drug Screening Assays Antitumor |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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