Dataset Information

Independent Generation and Reactivity of 2'-Deoxyguanosin-N1-yl Radical.

ABSTRACT: 2'-Deoxyguanosin-N1-yl radical (dG(N₁-H)^•) is the thermodynamically favored one-electron oxidation product of 2'-deoxyguanosine (dG), the most readily oxidized native nucleoside. dG(N₁-H)^• is produced by the formal dehydration of a hydroxyl radical adduct of dG as well as by deprotonation of the corresponding radical cation. dG(N₁-H)^• were formed as a result of the indirect and direct effects of ionizing radiation, among other DNA damaging agents. dG(N₁-H)^• was generated photochemically (λ_max = 350 nm) from an N-aryloxy-naphthalimide precursor (3). The quantum yield for photochemical conversion of 3 is ∼0.03 and decreases significantly in the presence O₂, suggesting that bond scission occurs from a triplet excited state. dG is formed quantitatively in the presence of excess β-mercaptoethanol. In the absence of a reducing agent, dG(N₁-H)^• oxidizes 3, decreasing the dG yield to ∼50%. Addition of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) as a sacrificial reductant results in a quantitative yield of dG and two-electron oxidation products of 8-oxodGuo. N-Aryloxy-naphthalimide 3 is an efficient and high-yielding photochemical precursor of dG(N₁-H)^• that will facilitate mechanistic studies on the reactivity of this important reactive intermediate involved in DNA damage.

SUBMITTER: Zheng L

PROVIDER: S-EPMC7334105 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Independent Generation and Reactivity of 2'-Deoxyguanosin-N1-yl Radical.

Zheng Liwei L Greenberg Marc M MM

The Journal of organic chemistry 20200611 13

2'-Deoxyguanosin-N1-yl radical (dG(N1-H)•) is the thermodynamically favored one-electron oxidation product of 2'-deoxyguanosine (dG), the most readily oxidized native nucleoside. dG(N1-H)• is produced by the formal dehydration of a hydroxyl radical adduct of dG as well as by deprotonation of the corresponding radical cation. dG(N1-H)• were formed as a result of the indirect and direct effects of ionizin ...[more]

PMID: 32525316

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Project description:Ubiquitous environmental agents [e.g., polynuclear aromatic hydrocarbons (PAHs) and their nitrated derivatives (NO(2)-PAHs)] that are known to induce mammary cancer in rodents are regarded as potential human risk factors for inducing analogous human cancers. Although 6-nitrochrysene (6-NC) is less abundant than other NO(2)-PAHs in the environment, it is the most potent mammary carcinogen in the rat; its carcinogenic potency is not only higher than that of the carcinogenic PAH, benzo[a]pyrene (B[a]P), but also of the well-known carcinogenic heterocylic aromatic amine, 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP). Studies in rats and in vitro assays have indicated that 6-NC can be activated by simple nitroreduction leading to the formation of 6-hydroxylaminochrysene (N-OH-6-AC); this metabolite yielded N-(deoxyguanosin-8-yl)-6-aminochrysene (N-[dG-8-yl]-6-AC) and 5-(deoxyguanosin-N(2)-yl)-6-aminochrysene (5-[dG-N(2)-yl]-6-AC. These lesions are likely to cause mutations if they are not removed by cellular defense mechanisms before DNA replication occurs. However, nothing is known about the susceptibility of these adducts to nucleotide excision repair (NER), the major cellular repair system that removes bulky adducts. In order to address this issue, we synthesized the N-(dG-8-yl)-6-AC and 5-(dG- N(2)-yl)-6-AC lesions and site-specifically inserted these lesions into 135-mer DNA duplexes. These constructs were incubated with NER-competent nuclear extracts from human HeLa cells. The efficiency of repair of these lesions was ∼ 8 times less efficient than that in the case of the well-known and excellent substrate of NER, the intrastrand cross-linked cis-diaminodichloroplatinum II adduct in double-stranded DNA (cis-Pt), but similar to N(2)-dG adducts derived from the (+)-bay region diol epoxide of B[a]P [(+)-trans-B[a]P-N(2)-dG]. The results support the hypothesis that the N-(dG-8-yl)-6-AC and 5-(dG-N(2)-yl)-6-AC lesions may be slowly repaired and thus persistent in mammalian tissue which could, in part, account for the potent tumorigenic activity of 6-NC in the rat mammary gland.

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Dataset Information

Independent Generation and Reactivity of 2'-Deoxyguanosin-N1-yl Radical.

Publications

Independent Generation and Reactivity of 2'-Deoxyguanosin-<i>N</i>1-yl Radical.

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