Influence of Chlorine Substitution on the Hydrolytic Stability of Biaryl Ether Nucleoside Adducts Produced by Phenolic Toxins
journal contributionposted on 19.07.2013, 00:00 by Michael S. Kuska, Mohadeseh Majdi Yazdi, Aaron A. Witham, Heidi A. Dahlmann, Shana J. Sturla, Stacey D. Wetmore, Richard A. Manderville
A kinetic study is reported for the acid-catalyzed hydrolysis of oxygen (O)-linked biaryl ether 8-2′-deoxyguanosine (dG) adducts produced by phenolic toxins following metabolism into phenoxyl radical intermediates. Strikingly, the reaction rate of hydrolysis at pH 1 decreases as electron-withdrawing chlorine (Cl) substituents are added to the phenoxyl ring. The Hammett plot for hydrolysis at pH 1 shows a linear negative slope with ρX = −0.65, implying that increased Cl-substitution diminishes the rate of hydrolysis by lowering N7 basicity. Spectrophotometric titration provided an N7H+ pKa value of 1.1 for the unsubstituted adduct 8-phenoxy-dG (Ph-O-dG). Model pyridine compounds suggest N7H+ pKa values of 0.92 and 0.37 for 4-Cl-Ph-O-dG and 2,6-dichloro-Ph-O-dG (DCP-O-dG), respectively. Density functional theory (DFT) calculations also highlight the ability of the 8-phenoxy substituent to lower N7 basicity and predict a preference for N3-protonation for highly chlorinated O-linked 8-dG adducts in water. The calculations also provide a rationale for the hydrolytic reactivity of O-linked 8-dG adducts in the gas-phase, as determined using electrospray mass spectrometry (ESI-MS). The inclusion of our data now establishes that the order of hydrolytic reactivity at neutral pH for bulky 8-dG adducts is N-linked > C-linked > O-linked, which correlates with their relative ease of N7-protonation.