Hypoxia-selective antitumor agents. 11. Chlorambucil N-oxide: a reappraisal of its synthesis, stability, and selective toxicity for hypoxic cells.
The potential hypoxia-selective cytotoxin 4-[4'-[N,N-bis(2"-chloroethyl)amino]phenyl]butanoic acid N-oxide (chlorambucil N-oxide, 4) was synthesized and characterized as its hydrochloride salt. This compound was shown to be unstable, decomposing in some organic solvents to the hydroxylamine 4-[4'-[N-(2"-chloroethoxy)-N-(2"-chloroethyl)amino]phenyl]butanoic acid (11) by a mechanism previously demonstrated for aliphatic mustard N-oxides and under aqueous conditions to a more complex mixture, of which the predominant components were the monochloroethyl derivative 7 and formaldehyde. Comparison of NMR spectra showed that a recent published synthesis of 4 in fact resulted in the rearrangement product 11, indicating that recent reported investigations of the hypoxia-selective cytotoxicity and metabolism of chlorambucil N-oxide have examined this rearrangement product rather than 4. In a clonogenic assay, 4 was less cytotoxic against AA8 cells than was chlorambucil, but the effect of oxygen on cytotoxicity was no greater than for chlorambucil itself.
Tercel
M
M
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Wilson
W R
WR
Denny
W A
WA
D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D003470:Culture Media; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000860:Hypoxia; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D013056:Spectrophotometry, Ultraviolet
D003470:Culture Media; D003497:Cyclic N-Oxides; D002699:Chlorambucil; C087810:chlorambucil N-oxide