Bioactivation of the antitumor drugs 9-hydroxyellipticine and derivatives by a peroxidase-hydrogen peroxide system.
Hydroxylation in position 9 (see Table I) of various antitumor drugs derived from ellipticine results, in most cases, in the possible further oxidation of the hydroxylated drugs into free radicals and quinone products in the presence of a peroxidase-H2O2 system. Except for the N6-methyl derivative, free radicals of hydroxyellipticines do not react with neighboring molecules. However, quinone products have been found to be strong electrophilic molecules. They can oxidize NADH into NAD+ through a nonenzymatic process, and, moreover, quinone from N2-methyl-9-hydroxyellipticine may undergo a nucleophilic attack, resulting in an irreversible binding of the drug to bovine serum albumin. Among the drugs tested, those which can be oxidized by peroxidase-H2O2 exhibit the most cytotoxic effect of L1210 cells in vitro.
D000470:Alkaloids / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001711:Biotransformation; D004611:Ellipticines / Q000378:metabolism*; D006861:Hydrogen Peroxide; D051379:Mice; D010084:Oxidation-Reduction; D010544:Peroxidases; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000970:Antineoplastic Agents; D004611:Ellipticines; C008009:9-hydroxyellipticine; D006861:Hydrogen Peroxide; D010544:Peroxidases