Synthesis and characterization of N-demethylated metabolites of malachite green and leucomalachite green.

Abstract

Malachite green (MG), a triphenylmethane dye used to treat fungal and protozoan infections in fish, undergoes sequential oxidation to produce various N-demethylated derivatives (monodes-, dides(sym)-, dides(unsym)-, trides-, and tetrades-) both before and after reduction to leucomalachite green (LMG). The close structure resemblance of the metabolites with aromatic amine carcinogens implicates a potential genotoxicity from exposure to MG. The availability of the synthetic standards is important for metabolic and DNA adduct studies of MG. This paper describes a simple and versatile method for the synthesis of MG, LMG, and their N-demethylated metabolites. The synthesis involves a coupling of 4-(dimethylamino)benzophenone or 4-nitrobenzophenone with the aryllithium reagents derived from appropriately substituted 4-bromoaniline derivatives, followed by treatment with HCl in methanol. The resulting cationic MG and their leuco analogues showed systematic UV/vis spectral and tandem mass fragmentation patterns consistent with sequential N-demethylation. The extensive (1)H and (13)C spectral assignments of the metabolites were aided by the availability of (13)C(7)-labeled MG and LMG. The results indicate the existence of a resonance structure with the cationic charge located in the central methane carbon (C(7)). The synthetic procedure is general in scope so that it can be extended to the preparation of N-demethylated metabolites of other structurally related N-methylated triphenylmethane dyes.

• Authors: Bongsup P Cho, Tianle Yang, Lonnie R Blankenship, Joanna D Moody, Mona Churchwell, Frederick A Beland, Sandra J Culp
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 16 Issue 3 Pg. 285-94 (Mar 2003) ISSN: 0893-228X [Print] United States
• PMID: 12641428 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Aniline Compounds
• Benzophenones
• Fungicides, Industrial
• Rosaniline Dyes
• malachite green
• leucomalachite green

Topics

• Aniline Compounds (chemical synthesis, chemistry, metabolism)
• Benzophenones (chemistry)
• Fungicides, Industrial (chemistry, metabolism)
• Magnetic Resonance Spectroscopy
• Mass Spectrometry (methods)
• Methylation
• Rosaniline Dyes (chemical synthesis, chemistry, metabolism)
• Spectrophotometry, Ultraviolet