New quinoxalinecarbonitrile 1,4-di-N-oxide derivatives as hypoxic-cytotoxic agents.
We report the synthesis and biological in vitro activities of 16 new 2-quinoxalinecarbonitrile 1,4-di-N-oxides. These compounds present new basic lateral chains (piperazines and anilines) in the 3 position as well as different substituents in the 6 and/or 7 positions of the quinoxaline ring. Among piperazine derivatives, 4b (a 7-chloro-3-(4-methylpiperazin-1-yl) derivative) was the most potent (P = 0.5 x10(-6) M). In general, aniline derivatives were more potent and selective than the former, compound 12b (with a 4-(methylphenyl)amino moiety in the 3 position and a chlorine atom in the 7 position) being the best one (P = 3 x 10(-6) 16).
Ortega
M A
MA
Department of Medicinal Chemistry, CIFA, Universidad de Navarra, 31080, Pamplona, Spain.
Morancho
M J
MJ
Martínez-Crespo
F J
FJ
Sainz
Y
Y
Montoya
M E
ME
López de Ceráin
A
A
Monge
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D008168:Lung; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C409475:7-chloro-3-(4-methylpiperazin-1-yl)-2-quinoxalinecarbonitrile-1,4-di-N-oxide; C409494:7-chloro-3-(methylphenyl)amino-2-quinoxalinecarbonitrile-1,4-di-N-oxide; C409493:7-chloro-3-phenylamino-2-quinoxalinecarbonitrile-1,4-di-N-oxide; D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D010879:Piperazines; D011810:Quinoxalines