Chemical transformations of 7,9-disubstituted purines and related heterocycles. Selective reduction of imines and immonium salts

Hecht, Sidney M.; Adams, Benjamin L.; Kozarich, John W.

doi:10.1021/jo00875a019

Cited by 43 publications

(66 citation statements)

References 11 publications

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“…After reduction there was no longer any detectable fluorescence. These data are consistent with reduction of the 7,8 double bond of the imidazole ring (7), and there is evidence in the literature for such NaBH4 reduction of N7 adducts and exchange of the C8 proton with the medium (17). It was also shown that partial reduction could also take place in the reaction mixture or with purified 6 (R' = CH3), with N-OH-AF acting as the reducing agent in this case ( Fig.…”

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confidence: 89%

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Mechanism of C8 alkylation of guanine residues by activated arylamines: evidence for initial adduct formation at the N7 position.

Humphreys

Kadlubar

Guengerich

1992

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

135

134

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Aromatic amines are bioactivated to electrophilic compounds that react with DNA, predominantly at the Ca position of guani bases. This site is weakly nudeephilic and it has been proposed that the Cs adduct Is the final product after initial N7-adduct formation. To consider this possibility, we reacted several C-substituted nine derivatives with N-acetoxy-2-aminofluorene, prepared in situ from 2-acetylsalicylic acid and N-hydroxy-2-aminofluorene. With C5,N'-dimethylguanine, an adduct was isolated in good yield that was consistent, by NMR and mass spectral characterization, with a structure involving cardnogen substitution at the N7 position of guanine and linked through the 2-aminofluorenyl nitrogen-N-(C6,N9-dimethylguanin-N7-yl)-2-aminofluorene. This adduct could be easily reduced with NaBH4, consistent with the proposed N7-adduct structre. The same reaction was also carried out with Cs-methylguanoslne and Cs-methyldeoxyguanosine and similar adducts were isolated. In contrast, C0-bromoguanosine reacted with N-acetoxy-2-ainlrene to yield the Cs-substituted arylamine adduct N-(guanosin-CO-yl)-2-aminofluorene directly. These products are uniquely consistent with a scheme in which Cs-adduct formation is preceded by an initial electrophilic substitution on the N7 atom, which is postulated to be a general reaction for activated arylamines and heterocyclic amines.Arylamines and heterocyclic amines constitute an extremely important class of chemical carcinogens (1, 2). They are bioactivated by oxidative and conjugative metabolism and the ultimate carcinogen is thought to be either the N-hydroxyarylamine or an O-esterified derivative formed by enzymatic conjugation (3) (Fig. 1). These compounds are strongly electrophilic and react through an SN2 mechanism with cellular DNA to yield adducted bases (4). The major adduct formed is generally at the C8 position of guanine residues (5). The C8 position is a favored site for certain radical addition reactions but seems weakly nucleophilic and does not react readily with other electrophilic species (6, 7). Indeed, most ofthe known guanyl-C8-substituted adducts are formed with radicals and arylamines (6), with a few exceptions that could proceed through alternative mechanisms but yield products that are not consistent with simple nucleophilic attack by the C8 atom [e.g., adducts derived from bifunctional reagents (8)]. This apparent contradiction has led to several proposals for alternative pathways for C8-adduct formation employing some type of intermediate site of adduction (9, 10). Because of the greater nucleophilicity and close proximity of the N7 atom, this would seem to be the most favored site for such an intermediate; i.e., 2. There have been several lines of evidence indirectly supporting such a view. Tarpley et al. (10) showed that there was rapid depurination upon treatment of DNA with activated arylamines, and Kohda et aL (11) showed that there was an increase in the amount of 7,8-dihydro-8-oxoguanine formed after reaction of DNA with activated 4-aminoquinol...

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confidence: 89%

“…In the case of the adducts derived from C8-methylguanosine and C8-methyldeoxyguanosine, the structural evidence is not as clear, due to equilibrium processes (most likely to be between the oxidized and reduced form of the adduct; see ref. 17). C8-Bromoguanosine produced a C8-AF adduct (4) directly upon reaction with N-OAc-AF.…”

mentioning

confidence: 99%

Mechanism of C8 alkylation of guanine residues by activated arylamines: evidence for initial adduct formation at the N7 position.

Humphreys

Kadlubar

Guengerich

1992

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

135

134

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“…Scissions of the imidazole ring under alkaline conditions have been observed for a number of 7,9-disubstituted purine derivatives (27,28). Several investigators have speculated (29) or provided preliminary evidence (17) concerning the formation of this product in aflatoxin-DNA adducts.…”

Section: Methodsmentioning

confidence: 99%

Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver.

Croy¹,

Essigmann²,

Reinhold³

et al. 1978

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

209

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The products of in vivo covalent binding of activated aflatoxin B1 (AFB1) to DNA have been investigated in rats. The principal covalent product formed in liver DNA of rats treated with AFB1 has been identified as 2,3-dihydro-2-(N7-guanyl)3hydroxy-aflatoxin B1. This compound was isolated from the liver DNA of rats dosed with AFB1 (2.0 mg/kg) in sufficient quantity for characterization by physicochemical techniques, including field-desorption mass spectrometry. This information together with results of chemical methylation of the compound proved that the major adduct formed between DNA and AFB1 in vivo is identical to that produced in vitro when AFB1 is incubated with DNA in the presence of a rat liver microsomal activating system. Quantitative studies of formation of this compound revealed a dose-ependent relationship between the level of its occurence in liver DNA and AFB1 doses over the range 0.125-1.0 mg/kg. Aflatoxin B1 (AFB1), a secondary fungal metabolite of several species of the genus Aspergillus, is acutely toxic to most animal species, although sensitivity varies widely. The rat, rainbow trout and duck are among the most susceptible to its toxic effects. AFB1 is also a potent hepatocarcinogen in these species (1) and is a potent mutagen in mammalian and bacterial cells (2-4). Epidemiological investigations in several human populations have revealed an association of increased incidences of hepatocellular carcinoma with increasing dietary contamination by AFB1 (5).Biological effects of AFB1 have been extensively studied in the rat. Acute doses of the toxin in this species produce both morphological and biochemical alterations primarily associated with the liver (6). Reversible inhibition of RNA synthesis has been demonstrated in vivo (7,8) and has been shown to be temporally associated with nucleolar segregation (9). DNA synthesis is also reversibly inhibited in normal (10) and partially hepatectomized (8, 11) animals following acute doses of the toxin.Investigations of various in vitro models have demonstrated the requirement for metabolic conversion of AFB1 to an active derivative which interacts covalently with DNA (12) and results in alterations of normal biochemical processes associated with it such as transcription and replication (8).Covalent binding of AFB1 to DNA in vitro is dependent on microsomal conversion of AFB1 to the reactive 2,3-exo-epoxide. Although this labile molecular species has not been isolated, much indirect evidence has accumulated to substantiate its transient existence (13,14). Covalent binding in vivo to nucleophilic atoms in proteins and nucleic acids is also thought to be mediated through metabolic activation to this reactive compound (15). Identification of the reactive sites in these macromolecules and the covalent compounds formed with AFB1 may provide a more complete understanding of its biological effects and provide further information on which to base hypotheses concerning the mechanisms underlying its carcinogenic properties.The nucleophilic sites of intera...

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“…Alkylation of the N7 position of guanine and adenine in DNA triggers base-catalyzed imidazole ring opening and the formation of N 5 -substituted formamidopyrimidine (N 5 -R-FAPy) lesions. Me-FAPy-dG adducts induced by exposure to methylating agents and AFB-FAPy-dG lesions formed by aflatoxin B 1 have been shown to persist in cells and to contribute to toxicity and mutagenicity.…”

mentioning

confidence: 99%

Chemical Biology of N⁵-Substituted Formamidopyrimidine DNA Adducts

Pujari

Tretyakova

2016

Chem. Res. Toxicol.

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DNA nucleobases are the prime targets for chemical modifications by endogenous and exogenous electrophiles. Alkylation of the N7 position of guanine and adenine in DNA triggers base-catalyzed imidazole ring opening and the formation of N5-substituted formamidopyrimidine (N5-R-FAPy) lesions. Me-FAPy-dG adducts induced by exposure to methylating agents and AFB-FAPy-dG lesions formed by aflatoxin B1 have been shown to persist in cells and to contribute to toxicity and mutagenicity. In contrast, the biological outcomes of other N5-substituted FAPy lesions have not been fully elucidated. To enable their structural and biological evaluation, N5-R-FAPy adducts must be site-specifically incorporated into synthetic DNA strands using phosphoramidite building blocks, which can be complicated by their unusual structural complexity. N5-R-FAPy exist as a mixture of rotamers and can undergo isomerization between α, β anomers and furanose-pyranose forms. In this Perspective, we will discuss the main types of N5-R-FAPy adducts and summarize the strategies for their synthesis and structural elucidation. We will also summarize the chemical biology studies conducted with N5-R-FAPy-containing DNA to elucidate their effects on DNA replication and to identify the mechanisms of N5-R-FAPy repair.

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Chemical transformations of 7,9-disubstituted purines and related heterocycles. Selective reduction of imines and immonium salts

Cited by 43 publications

References 11 publications

Mechanism of C8 alkylation of guanine residues by activated arylamines: evidence for initial adduct formation at the N7 position.

Mechanism of C8 alkylation of guanine residues by activated arylamines: evidence for initial adduct formation at the N7 position.

Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver.

Chemical Biology of N⁵-Substituted Formamidopyrimidine DNA Adducts

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Chemical transformations of 7,9-disubstituted purines and related heterocycles. Selective reduction of imines and immonium salts

Cited by 43 publications

References 11 publications

Mechanism of C8 alkylation of guanine residues by activated arylamines: evidence for initial adduct formation at the N7 position.

Mechanism of C8 alkylation of guanine residues by activated arylamines: evidence for initial adduct formation at the N7 position.

Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver.

Chemical Biology of N5-Substituted Formamidopyrimidine DNA Adducts

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Chemical Biology of N⁵-Substituted Formamidopyrimidine DNA Adducts