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 vit ro bioreductive antitumor activity. A time-dependent hypoxic different ial was observed when EMT6 cells were exposed to CHLN-O in the presenc e of rat liver microsomes and reducing equivalents. The cytotoxicity o f the N-oxide was potentiated under hypoxia, and augmented further by a combination of low pH and hypoxia. Metabolic studies were also under taken, which utilized previously described HPLC methodology for the an alysis of CHLN-O loss from biological fluids. These demonstrated the r equirement for microsomal enzymes and reducing equivalents, and also i llustrated the time-dependent manner of CHLN-O loss from isolated micr osomal preparations.