Hypoxia-Selective Antitumor Agents. 11. Chlorambucil N-Oxide: A Reappraisal of Its Synthesis, Stability, and Selective Toxicity for Hypoxic Cells

Article abstract of DOI:10.1021/jm00007a021

The potential hypoxia-selective cytotoxin 4-<4'-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'-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.