DNA cleavage by Di- and trihydroxyalkylbenzenes. Characterization of products and the roles of O-2, Cu(II), and alkali

Several 5-alkyl-1,3-dihydroxybenzene (5-alkylresorcinol, 1) and 6-alkyl-1,2,4-trihydroxybenzene (2) derivatives were prepared and used to study the mechanism by which such compounds effect Cu(II)-dependent DNA strand scission. Comparison of the methyl, n-pentyl, n-undecyl, and n-hexadecyl derivatives in each structural series indicated that the efficiency of DNA cleavage increased with increasing length of the alkyl substituent. DNA cleavage by the 5-alkylresorcinols appears to involve initial oxygenation of the benzene nucleus, a process that occurs readily at alkaline pH in the presence of Cu2+ and O-2. The resulting trihydroxylated benzenes mediate DNA cleavage in a reaction dependent on the presence of both Cu2+ and O-2. The mechanism appears to involve reduction of CU2+ by the trihydroxybenzene moiety in 2, with subsequent formation of reactive oxygen species. The ability of catalase and dimethyl sulfoxide to suppress DNA strand scission is consistent with the intermediacy of H2O2 and (OH)-O-. in the DNA strand scission process.