The Ultimate Carcinogen, O‐Acetyl‐N‐(2‐fluorenyl)hydroxylamine (“N‐Acetoxy‐2‐aminofluorene”), and Its Reaction in vitro to Form 2‐[N‐(Deoxyguanosin‐8‐yl)amino] fluorene

Bosold, Ferdinand; Boche, Gernot

doi:10.1002/anie.199000631

Cited by 29 publications

(14 citation statements)

References 16 publications

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“…Since the O -acetylation of N -arylhydroxylamines has been implicated as a major metabolic activation pathway for aromatic amines (), we tested N -acetoxyarylamines and their synthetic equivalents, N -pivaloxyarylamines, as key reactive intermediates. This strategy has been applied previously by Boche and co-workers to the synthesis of dG-C8-Ar adducts from the polyarylamine carcinogens 4-aminobiphenyl, 2-naphthylamine, and 2-aminofluorene in low to moderate yields ( − ). The same investigators have shown that the procedure can be extended to some monoarylamines, specifically aniline () and anilines monosubstituted in the para position ().…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and Conformational Analysis of DNA Adducts from Methylated Anilines Present in Tobacco Smoke

Marques

Mourato

Santos

et al. 1996

Chem. Res. Toxicol.

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The ability of a series of aromatic amines present in tobacco smoke (2-, 3-, and 4-methylaniline, 2,3- and 2,4-dimethylaniline) to bind to DNA has been investigated by reacting N-(acyloxy)arylamines with dG, dG nucleotides, and DNA. The predominant products from reactions with dG and the nucleotides were characterized as N-(deoxyguanosin-8-yl)arylamines by spectroscopic and HPLC methods. HPLC and spectroscopic analyses of the modified DNA indicated the same adducts. Analyses of the 1H and 13C NMR spectra suggested that the adducts containing a methyl substituent ortho to the arylamine nitrogen had a higher percentage of syn conformers. This observation was supported by theoretical simulation studies that indicated substantial percentages of low energy syn conformers, increasing with the substitution pattern in the order para < meta < ortho < ortho,para < ortho,meta. The results demonstrate that, although single-ring arylamines are considered weak carcinogens, their electrophilic N-acetoxy derivatives, which are plausible metabolic intermediates, react with DNA to yield covalent adducts structurally identical to those derived from carcinogenic polyarylamines, such as 2-aminofluorene and 4-aminobiphenyl. Furthermore, the conformational perturbation induced in DNA by the formation of the monoarylamine-DNA adducts, especially those with an ortho substituent, may contribute to the biological activities of these compounds.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and Conformational Analysis of DNA Adducts from Methylated Anilines Present in Tobacco Smoke

Marques

Mourato

Santos

et al. 1996

Chem. Res. Toxicol.

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“…Arylhydroxylamines are highly reactive and hence cytotoxic, mutagenic, and carcinogenic. Interestingly, the formation of nitrenium/carbenium cations from hydroxylaminoarenes plays an important role in these effects, because the reactive cations are also susceptible to nucleophilic attack by nucleic acid bases and other nucleophiles (7,8,38). Enzymes that convert arylhydroxylamines to harmless products are useful detoxification tools and are essential to survival for a biological system.…”

Section: Discussionmentioning

confidence: 99%

3-Hydroxylaminophenol Mutase from Ralstonia eutropha JMP134 Catalyzes a Bamberger Rearrangement

et al. 1999

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3-Hydroxylaminophenol mutase from Ralstonia eutrophaJMP134 is involved in the degradative pathway of 3-nitrophenol, in which it catalyzes the conversion of 3-hydroxylaminophenol to aminohydroquinone. To show that the reaction was really catalyzed by a single enzyme without the release of intermediates, the corresponding protein was purified to apparent homogeneity from an extract of cells grown on 3-nitrophenol as the nitrogen source and succinate as the carbon and energy source. 3-Hydroxylaminophenol mutase appears to be a relatively hydrophobic but soluble and colorless protein consisting of a single 62-kDa polypeptide. The pI was determined to be at pH 4.5. In a database search, the NH2-terminal amino acid sequence of the undigested protein and of two internal sequences of 3-hydroxylaminophenol mutase were found to be most similar to those of glutamine synthetases from different species. Hydroxylaminobenzene, 4-hydroxylaminotoluene, and 2-chloro-5-hydroxylaminophenol, but not 4-hydroxylaminobenzoate, can also serve as substrates for the enzyme. The enzyme requires no oxygen or added cofactors for its reaction, which suggests an enzymatic mechanism analogous to the acid-catalyzed Bamberger rearrangement.

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“…This type of DNA damage can, under certain circumstances, convert a healthy cell into a cancer cell. This proposal has been discussed at length in a number of recent articles and reviews [3][4][5][6][7][8][9][10] and it will not be considered further here other than to note that the relevant reactions appear to be characteristic of the singlet state (see below).…”

Section: Introductionmentioning

confidence: 99%

Singlet and triplet states in the reactions of nitrenium ions

Falvey

1999

J. Phys. Org. Chem.

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Nitrenium ions (R-N-R ) are reactive intermediates which are isoelectronic with carbenes. Like the more familiar carbenes, nitrenium ions have low-energy singlet and triplet states. Recent experiments have been directed at understanding how singlet and triplet nitrenium ions differ in their chemical reactivity. Singlet nitrenium ions typically react rapidly with nucleophiles whereas the triplet nitrenium ions tend to abstract H atoms. Several specific cases are discussed including the parent system, NH 2 , and several arylnitrenium ions.

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The Ultimate Carcinogen, O‐Acetyl‐N‐(2‐fluorenyl)hydroxylamine (“N‐Acetoxy‐2‐aminofluorene”), and Its Reaction in vitro to Form 2‐[N‐(Deoxyguanosin‐8‐yl)amino] fluorene

Cited by 29 publications

References 16 publications

Synthesis, Characterization, and Conformational Analysis of DNA Adducts from Methylated Anilines Present in Tobacco Smoke

Synthesis, Characterization, and Conformational Analysis of DNA Adducts from Methylated Anilines Present in Tobacco Smoke

3-Hydroxylaminophenol Mutase from Ralstonia eutropha JMP134 Catalyzes a Bamberger Rearrangement

Singlet and triplet states in the reactions of nitrenium ions

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