Peroxidase-catalysed oxidation of N2,N6-dimethyl-9-hydroxyellipticinium acetate. Evidence for the formation of an electrophilic quinone-iminium derivative.
The activation of N2,N6-dimethyl-9-hydroxyellipticinium acetate (DMHE) by a peroxidase-H2O2 system leads to a reactive orthoquinone, or in the presence of a nucleophile like alanine, to adducts with a proposed benzoxazole structure. The stoichiometric and pH metric studies support the generation of a bicationic electrophilic intermediate, namely a quinone-iminium. Since no N6-demethylation occurs during the oxidation process, DMHE is not a prodrug of Celiptium (N2-methyl-9-hydroxy-ellipticinium acetate), but the high electrophilic properties of the species generated might explain its great cytotoxicity and antitumor properties. These results extend the possibility for N6-methyl ellipticine derivatives of a biooxidative activation which can play a role in their cytotoxicity.
D000409:Alanine / Q000378:metabolism; D000470:Alkaloids / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D004611:Ellipticines / Q000378:metabolism*; D006735:Horseradish Peroxidase / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000378:metabolism*
D000470:Alkaloids; D004611:Ellipticines; C027767:elliptinium; C053305:N(2),N(6)-dimethyl-9-hydroxyellipticinium; D006735:Horseradish Peroxidase; D010544:Peroxidases; D000409:Alanine