One-electron oxidation of .alpha.-monoalkoxyalkyl radicals by tetranitromethane via an intermediate adduct. Influence of the radical structure on the rate of decomposition of the adduct

Eibenberger, J.; Schulte‐Frohlinde, D.; Steenken, S.

doi:10.1021/j100444a005

Cited by 51 publications

(25 citation statements)

References 12 publications

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“…Tests for radicals which oxidize N,N,N',N'-tetramethylphenylene diamine (TMPD) In a N 2 0-saturated aqueous solution of 3mM 5,6-dihydrouracil (DHU) containing 5 x 10-M TMPD at pH -8, there is competition between DHU and N 2 0 for e as well as between DHU and TMPD for OH radicals (for rate constants see Farhataziz and Ross (1977)). Thus under these conditions 10 per cent of e is scavenged by DHU directly, G(OH) 52 (Schuler et al 1981), from which 10 per cent of the OH radicals react directly with TMPD.…”

Section: Resultsmentioning

confidence: 99%

“…The 28 MeV Van-de-Graaff electron accelerator and the optical and AC-conductivity detection techniques have been described previously (Getoff and Schw6rer 1970, Asmus and Janata 1982, Hazra and Steenken 1983.…”

Section: Methodsmentioning

confidence: 99%

“…It is known from previous work by Steenken and co-workers (Fujita andSteenken 1981, Hazra andSteenken 1983) that 5-yl radicals of pyrimidine bases oxidize N,N,N',N'-tetramethylphenylene diamine to the corresponding radical cation and that the 6-yl radicals have reducing properties which can quantitatively reduce tetranitromethane to the nitroform anion. It is the purpose of this paper to exploit similar oxidizing and reducing properties of radicals derived from reactions of OH radicals with dihydropyrimidines in order to determine the relative abundance of these radicals.…”

Section: Introductionmentioning

confidence: 99%

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Site of OH Radical Attack on Dihydrouracil and Some of Its Methyl Derivatives

Schuchmann

Steenken

Wroblewski

et al. 1984

International Journal of Radiation Biology and Related Studies

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The site of attack of OH radicals on dihydrouracil and five of its methylated derivatives was determined by pulse radiolysis using N,N,N',N'-tetramethylphenylenediamine (TMPD) to detect oxidizing radicals and tetranitromethane (TNM) as well as K3Fe(CN)6 to detect reducing radicals. In the case of dihydrouracil OH radicals abstract preferentially an H atom at C(6) to give the 6-yl radical (greater than or equal to 90 per cent) which at pH approximately 6.5 reduces TNM and K3Fe(CN)6 at almost diffusion-controlled rates. Only a small fraction of OH radicals abstract the H atom at C(5) (less than or equal to 10 per cent). The resulting 5-yl radical oxidizes TMPD to TMPD+ at pH 7-8. With the methylated derivatives of dihydrouracil, OH radicals react less selectively, especially in the case of N(1)-methyl derivatives. This methyl group is activated to a similar degree as the methylene group at C(6). In 1-Medihydrouracil the yield of N(1)-CH2 radicals is about 29 per cent, which has been deduced from the yield of formaldehyde formed after oxidation of this radical by TNM at pH approximately 6.5 and the subsequent hydrolysis. Radicals at the other methyl substituents are generated to a lesser extent (less than or equal to 10 per cent) and are relatively unreactive towards oxidizing agents such as TNM and K3Fe(CN)6 as well as towards the reducing agent TMPD. Although methyl substitution opens new routes for OH attack the preferred site of H abstraction remains C(6) (greater than 60 per cent).

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Site of OH Radical Attack on Dihydrouracil and Some of Its Methyl Derivatives

Schuchmann

Steenken

Wroblewski

et al. 1984

International Journal of Radiation Biology and Related Studies

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“…The carbon- centered radical at C-5' (structure 1), produced by hydrogenatom abstraction by a radical species of NCS-Chrom, forms a labile nitroxyl radical adduct (structure 2) with misonidazole (RNO2) (reaction 1). The addition of carboncentered radicals to the oxygen of the nitro group of tetranitromethane and nitrobenzenes to give intermediate nitroxide radicals has been documented by electron spinresonance spectroscopy and pulse-radiolysis methods (13)(14)(15). While such adducts can act as intermediates in one-electron oxidations, as has been described in radiationsensitization reactions with pyrimidines and their derivatives (15), they also can undergo fragmentation (reaction 2) to form oxy radicals (structure 3) and the nitroso reduction product of misonidazole, a two-electron process (16).…”

Section: Discussionmentioning

confidence: 99%

3'-Formyl phosphate-ended DNA: high-energy intermediate in antibiotic-induced DNA sugar damage.

Chin

Kappen

Goldberg

1987

Proc. Natl. Acad. Sci. U.S.A.

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Under anaerobic conditions where the nitroaromatic radiation-sensitizer misonidazole substitutes for dioxygen, DNA strand breakage (gaps with phosphate residues at each end) by the nonprotein chromophore of the antitumor antibiotic neocarzinostatin (NCS-Chrom) is associated with the generation of a reactive form of formate from the C-5' of deoxyribose of thymidylate residues. Such lesions account for a minority (10-15%) of the strand breakage found in the aerobic reaction without misonidazole. Amino-containing nucleophiles such as tris(hydroxymethyl)aminomethane (Tris) and hydroxylamine act as acceptors for the activated formate. The amount of [3H formyl hydroxamate produced from DNA labeled with [5'-3H]thymidine is comparable to the spontaneously released thymine. During the course of the reaction, misonidazole undergoes a DNA-dependent reduction and subsequent conjugation with glutathione used to activate NCSChrom. From these and earlier results, we propose a possible mechanism in which the carbon-centered radical formed at C-5' by hydrogen atom abstraction by thiol-activated NCSChrom reacts anaerobically with misonidazole to form a nitroxyl-radical-adduct intermediate, which fragments to produce an oxy radical at C-5'. j3-Fragmentation results in cleavage between C-5' and C-4' with the generation of 3'-formyl phosphate-ended DNA, a high-energy form of formate, which spontaneously hydrolyzes, releasing formate and creating a 3'-phosphate end, or transfers the formyl moiety to available nucleophiles. A similar mechanism, involving dioxygen addition, is probably responsible for the 10-15% DNA gap formation in the aerobic reaction.as to position the reactive ring system containing the two acetylenic bonds close to the C-5' of deoxyribose of mainly thymidylate residues.Upon activation by thiol [glutathione in the cell (2)], the DNA-bound drug is converted into a species, presumably free-radical form, that abstracts a hydrogen atom from C-5' to generate a carbon-centered radical, whether or not dioxygen is present (3). Addition of dioxygen to the radical at C-5' forms a peroxyl radical species that undergoes reduction by thiol to generate a DNA strand break with a nucleoside 5'-aldehyde group at the 5' end and a phosphate at the 3' end.Such lesions account for more than 80% of the strand breaks produced (4). The remaining 10-15% of the strand breaks are actually gaps with phosphates at both ends. The mechanism for their production has not been clear, although it has been thought to be related to the formation of formate from C-5' (5). In addition to single-strand breaks, DNA bases (mainly thymine) are also released (6, 7), in part generating abasic sites. When nitroaromatic radiation sensitizers, such as misonidazole, are substituted for dioxygen in the reaction, gaps with phosphates at both ends constitute the main form of DNA breakage (8), and this is associated with base (mainly thymine) release and a 4-to 5-fold increase (over the aerobic reaction) in the release of a soluble material labeled with tri...

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“…Although the a-hydroxyalkyl radicals are very strong one electron reducing agents (12,(33)(34)(35)(36)(37), typically the reaction which forms the organometallic species, at least formally, must be considered a one electron oxidation of the metal (38), Thus, Ni(I) reacted with «CH^OH forms Ni^^-CHgOH. Also, Cr^^ is considered to be oxidized to the 1 ?…”

Section: +mentioning

confidence: 99%

Mechanistic chemistry of some transition metal complexes

Kirker¹

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One-electron oxidation of .alpha.-monoalkoxyalkyl radicals by tetranitromethane via an intermediate adduct. Influence of the radical structure on the rate of decomposition of the adduct

Cited by 51 publications

References 12 publications

Site of OH Radical Attack on Dihydrouracil and Some of Its Methyl Derivatives

Site of OH Radical Attack on Dihydrouracil and Some of Its Methyl Derivatives

3'-Formyl phosphate-ended DNA: high-energy intermediate in antibiotic-induced DNA sugar damage.

Mechanistic chemistry of some transition metal complexes

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