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FIGURE 7.3 Ellipticine metabolites and their binding to DNA

in spite of its high electrophilicity, this intermediate seems not to be covalently bonded to DNA. More recent studies have proved that DNA binding is associated to other metabolites, including the N-oxide 7.3 and the hydroxymethyl derivative 7.4, which can be tentatively assumed to react through the intermediacy of stabilized cation 7.5 to give the DNA-alkylated product 7.6, as shown in Fig. 7.3.9 Because of the higher efficiency of cations as intercalating agents, some N-2 quaternized ellipticine analogues were assayed, among which the most interesting was N-methyl-9-hydroxyellipticinium (NMHE). Its quinonimine 7.7 is more reactive than its previously mentioned analogue from ellipticine (7.2) because of the presence of the strongly electron-withdrawing cationic heterocyclic nitrogen atom, and has been shown to react with a variety of biologically relevant nucleo-philes at its C-10 position to give adducts 7.9 (Fig. 7.4). However, a correlation between the in vivo antitumor activity of NMHE and the formation of covalent adducts has not been established; in fact, it has been shown that the extent of

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