Synthesis and biological evaluation of new 2-arylcarbonyl-3-trifluoromethylquinoxaline 1,4-di-N-oxide derivatives and their reduced analogues.
As a continuation of our research in the quinoxaline 1,4-di-N-oxide new series of 2-arylcarbonyl-3-trifluoromethylquinoxaline, 1,4-di-N-oxide derivatives have been synthesized and evaluated in a full panel of 60 human tumor cell lines. Selective reductions were carried out on two compounds which allowed us to determine the compound structures by comparison of the 1H NMR spectra. In general, all the di-N-oxidized compounds showed good cytotoxic parameters. The best activity was observed in derivatives with electron-withdrawing groups in position 6 or 7 on the quinoxaline ring and in the unsubstituted analogues, whereas loss of one or two oxygens reduced the cytotoxicity. The best five compounds were selected for evaluation for the in vivo hollow fiber assays. In vitro studies reveal that compound 5h efficiently generates reactive oxygen species via redox cycling in the presence of the NADPH/cytochrome P450 enzyme system, providing a plausible molecular mechanism for the observed aerobic cytotoxicity of these quinoxaline N-oxides.
Solano
Beatriz
B
Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), University of Navarra, c/Irunlarrea s/n, 31080 Pamplona, Spain.
Junnotula
Venkatraman
V
Marín
Adoración
A
Villar
Raquel
R
Burguete
Asunción
A
Vicente
Esther
E
Pérez-Silanes
Silvia
S
Aldana
Ignacio
I
Monge
Antonio
A
Dutta
Sanjay
S
Sarkar
Ujjal
U
Gates
Kent S
KS
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D009243:NAD; D003577:Cytochrome P-450 Enzyme System