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

Abstract

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 N(7) basicity. Spectrophotometric titration provided an N(7)H(+) pKa value of 1.1 for the unsubstituted adduct 8-phenoxy-dG (Ph-O-dG). Model pyridine compounds suggest N(7)H(+) 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 N(7) basicity and predict a preference for N(3)-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 N(7)-protonation.

Influence of the Linkage Type and Functional Groups in the Carcinogenic Moiety on the Conformational Preferences of Damaged DNA: Structural and Energetic Characterization of Carbon- and Oxygen-Linked C8-Phenolic-Guanine Adducts

“…For the PhO dG nucleoside adduct, detailed Monte Carlo conformational searches were previously used to identify the global minimum, 37 which adopts the syn orientation, the C ଶ′ -endo sugar pucker that is the most common pucker in B-DNA, the 5′-OH group forms a hydrogen bond with N 3 of guanine (∠(C ସ′ -C ହ′ -O-H) ~ 55°), and the 3′-OH group is directed towards C ଶ′ (∠(C ସ′ -C ହ′ -O-H) ~ 58°). The present work used this lowest energy structure to carry out subsequent PES scans to determine the flexibility of the PhO dG nucleoside adduct.…”

Chlorine substitution promotes phenyl radical loss from C8-phenoxy-2′-deoxyguanosine adducts: implications for biomarker identification from chlorophenol exposure

“…Increased Cl‐substitution diminished the rate of hydrolysis by lowering N7 basicity. These findings demonstrate that Cl‐substituted O‐linked C8‐dG adducts are hydrolytically stable compared to unsubstituted O‐linked derivatives, and other C‐linked C8‐dG adducts produced by phenoxyl radical intermediates . Our analysis of the nucleoside adducts using negative ESI uncovered a unique dissociation pathway for O‐linked C8‐dG adducts.…”

“…(b)). Attachment of electron‐withdrawing substituents to the phenyl ring increases the leaving‐group ability of the nucleobase by stabilizing the developing negative charge on N9 during glycosidic bond cleavage . The ortho ‐derivative 2‐Cl‐Ph‐O‐dG ( 3 ) (Fig.…”

“…O‐linked C8‐dG adducts (Ph‐O‐dG ( 1 ), 4‐Cl‐Ph‐O‐dG ( 2 ), 2‐Cl‐Ph‐O‐dG ( 3 ), 2,4‐DCP‐O‐dG ( 4 ), 2,4,6‐TCP‐O‐dG ( 5 ) and PCP‐O‐dG ( 6 )) were chemically synthesized, as outlined in detail . The benzyl derivative Bn‐O‐dG ( 7 ) was synthesized according to the literature .…”

Chlorine Functionalization of a Model Phenolic C8-Guanine Adduct Increases Conformational Rigidity and Blocks Extension by a Y-Family DNA Polymerase

“…All unmodified phosphoramidites (bz-dA-CE, ac-dC-CE, dmf-dG-CE, and dT-CE), activator (0. 25 10 They were converted into phosphoramidites (Scheme S1) using procedures for the synthesis of the [PhO]G phosphoramidite (see Supporting Information for experimental details and NMR spectra of synthetic intermediates) . 11 Oligonucleotide Synthesis and Purification.…”