Synthesis and bioreductive potential of a mono N-oxide derivative of the alkylating agent chlorambucil.
Chlorambucil N-oxide (CHLN-O) was synthesized and evaluated for in vitro bioreductive antitumor activity. A time-dependent hypoxic differential was observed when EMT6 cells were exposed to CHLN-O in the presence of rat liver microsomes and reducing equivalents. The cytotoxicity of the N-oxide was potentiated under hypoxia, and augmented further by a combination of low pH and hypoxia. Metabolic studies were also undertaken, which utilized previously described HPLC methodology for the analysis of CHLN-O loss from biological fluids. These demonstrated the requirement for microsomal enzymes and reducing equivalents, and also illustrated the time-dependent manner of CHLN-O loss from isolated microsomal preparations.
Kirkpatrick
D L
DL
Department of Chemistry, University of Regina, SK, Canada.
Schroeder
H L
HL
Chandler
K J
KJ
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003497:Cyclic N-Oxides; D002699:Chlorambucil; C087810:chlorambucil N-oxide