Influence of Chlorine Substitution on the Hydrolytic Stability of Biaryl Ether Nucleoside Adducts Produced by Phenolic Toxins

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• 作者：Michael S. Kuska ; Mohadeseh Majdi Yazdi ; Aaron A. Witham ; Heidi A. Dahlmann ; Shana J. Sturla ; Stacey D. Wetmore ; Richard A. Manderville
• 刊名：The Journal of Organic Chemistry
• 出版年：2013
• 出版时间：July 19, 2013
• 年：2013
• 卷：78
• 期：14
• 页码：7176-7185
• 全文大小：473K
• 年卷期：v.78,no.14(July 19, 2013)
• ISSN：1520-6904

文摘

A kinetic study is reported for the acid-catalyzed hydrolysis of oxygen (O)-linked biaryl ether 8-2鈥?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 蟻_X = 鈭?.65, implying that increased Cl-substitution diminishes the rate of hydrolysis by lowering N⁷ basicity. Spectrophotometric titration provided an N⁷H⁺ pK_a value of 1.1 for the unsubstituted adduct 8-phenoxy-dG (Ph-O-dG). Model pyridine compounds suggest N⁷H⁺ pK_a 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.