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: Charles M Keyari, Alison K Kearns, Nathan S Duncan, Emily A Eickholt, Geoffrey Abbott, Howard D Beall, Philippe Diaz
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 10 Pg. 3806-19 (May 23 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23574193 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Coloring Agents
• Indicators and Reagents
• Quinolines
• Tetrazolium Salts
• Thiazoles
• Cytochromes c
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human
• thiazolyl blue

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coloring Agents
• Cytochromes c (antagonists & inhibitors, metabolism)
• Drug Screening Assays, Antitumor
• Electrochemistry
• Humans
• Indicators and Reagents
• Magnetic Resonance Spectroscopy
• Microwaves
• Models, Molecular
• NAD(P)H Dehydrogenase (Quinone) (antagonists & inhibitors)
• Oxygen Consumption (drug effects)
• Quinolines (chemical synthesis, pharmacology)
• Structure-Activity Relationship
• Tetrazolium Salts
• Thiazoles