Hypoxia-selective antitumor agents. 11. Chlorambucil N-oxide: a reappraisal of its synthesis, stability, and selective toxicity for hypoxic cells.

Abstract

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.

• Authors: M Tercel, W R Wilson, W A Denny
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 38 Issue 7 Pg. 1247-52 (Mar 31 1995) ISSN: 0022-2623 [Print] United States
• PMID: 7707327 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Culture Media
• Cyclic N-Oxides
• Chlorambucil
• chlorambucil N-oxide

Topics

• Cell Survival (drug effects)
• Cells, Cultured
• Chlorambucil (analogs & derivatives, chemical synthesis, chemistry, toxicity)
• Culture Media
• Cyclic N-Oxides (chemical synthesis, chemistry, toxicity)
• Hypoxia
• In Vitro Techniques
• Magnetic Resonance Spectroscopy
• Oxidation-Reduction
• Spectrophotometry, Ultraviolet