Isolation and characterization of N-alkyl-N- (hydroxymethyl)nitrosamines from N-alkyl-N- (hydroperoxymethyl)nitrosamines by deoxygenation

Mochizuki, Masahito; Anjo, Takako; Okada, Masashi

doi:10.1016/s0040-4039(00)78747-8

Cited by 73 publications

(49 citation statements)

References 8 publications

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“…It is seen from Table 1 that 5 is somewhat more stable than 6 . This result is in agreement with experimental observations of Mochizuki et al that the E structures are more stable than the Z isomers (22). Moreover, NMR evidence confirms that E and Z forms are configurationally stable and do not readily interconvert (22).…”

Section: Ester Conjugates Of E-and Z-hydroxymethylmethylnitrosaminesupporting

confidence: 93%

“…This result is in agreement with experimental observations of Mochizuki et al that the E structures are more stable than the Z isomers (22). Moreover, NMR evidence confirms that E and Z forms are configurationally stable and do not readily interconvert (22). The N1N2 bond length does not show any significant change from 1 to 5 or 6 and neither do the other bond lengths.…”

Section: Ester Conjugates Of E-and Z-hydroxymethylmethylnitrosaminesupporting

confidence: 92%

“…and decomposition in aqueous solution Experimentally it is known that whereas E-and Zhydroxymethylmethylnitrosarnines have moderate stability in aprotic media, they decompose spontaneously to formaldehyde and methylnitrosamine or methanediazohydroxide, or its kinetic equivalent the methane diazonium ion (22). Possible alternative pathways were considered for this process and examined by quantum chemical methods.…”

Section: Stability Of Hydroxymethylmethylnitrosamine In Aprotic Mediamentioning

confidence: 99%

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Quantum chemical studies of alkyldinitrogen species implicated in nitrosamine carcinogenesis

Demeunynck¹,

Lown²,

Sapse³

1989

Can. J. Chem.

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. Can. J. Chem. 67, 625 (1989). Ab initio calculations (Hartree-Fock) at the level of 3-21G and 6-31G* as well as MP2/6-31G* have been performed on the carcinogen dimethylnitrosamine and its products of oxidative metabolism E-(and Z-) hydroxymethylmethylnitrosamines and certain ester conjugates. The E-and Z-hydroxymethylmethylnitrosamines are found to be close in energy and to be configurationally stable as is found experimentally. Alternative pathways are examined for the spontaneous decomposition of the primary metabolite in aqueous solution. Direct cleavage of E-hydroxymethylmethylnitrosamine to Z-methanediazohydroxide and formaldehyde is highly endothermic. Protonation of the NO group of the hydroxylated metabolite strongly stabilizes this species in contrast to nitrosoureas but in accord with experiment. Incorporation of water together with consideration of entropy effects satisfactorily accounts for the spontaneous exothermic decomposition of E-hydroxymethylmethylnitrosamine in aqueous media, as well as its relative stability in aprotic media. Ab initio calculations were also performed on selected nitrosoiminium ions which participate in the enzymatic activation and metabolism of certain dialkylnitrosamine carcinogens.Key words: carcinogenesis, dimethylnitrosamine, ab initio calculations, nitrosoiminium ions.

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Section: Ester Conjugates Of E-and Z-hydroxymethylmethylnitrosaminesupporting

confidence: 93%

Section: Ester Conjugates Of E-and Z-hydroxymethylmethylnitrosaminesupporting

confidence: 92%

Section: Stability Of Hydroxymethylmethylnitrosamine In Aprotic Mediamentioning

confidence: 99%

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Quantum chemical studies of alkyldinitrogen species implicated in nitrosamine carcinogenesis

Demeunynck¹,

Lown²,

Sapse³

1989

Can. J. Chem.

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“…The direct-acting mutagen formed in the presence of Fe 2+ -Cu 2+ -H 2 O 2 was not the α-hydroxynitrosamine, which is highly unstable in aqueous solution. 24) It is interesting that the mutagenicity of the oxidation products of NDB generated in the presence of Fe 2+ -Cu 2+ -H 2 O 2 produced the same alkylating damage observed with the α-hydroxynitrosamines.…”

Section: Discussionmentioning

confidence: 94%

Oxidation Products of N-nitrosodialkylamines Generated by Fenton's Reagent in the Presence of Copper Are Direct Acting Mutagens

Inami

Ishimura

Akaike

et al. 2010

JOURNAL OF HEALTH SCIENCE

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N-Nitrosodialkylamines, activated metabolically by cytochrome P450, possess mutagenic and carcinogenic activity. In this study, the hydroxyl radical, generated from Fenton's reagent, was used as an oxidant for the activation of the N-nitrosodialkylamines. Ethyl acetate extract from the reaction mixture which included Fe 2+ -Cu 2+ -H 2 O 2 and, were assayed for their mutagenicity in Salmonella typhimurium (S. typhimurium) TA1535 and Escherichia coli (E. coli) WP2 uvrA. Although Fenton's reagent (Fe 2+ -H 2 O 2 ) alone did not activate NMB, the addition of the copper ion to the reaction with Fenton's reagent (Fe 2+ -Cu 2+ -H 2 O 2 ) resulted in the production of mutagens. While the extracts of the reaction of NDM or NDE with Fe 2+ -Cu 2+ -H 2 O 2 were not mutagenic, those of NMP, NDP, NMB, or NDB with Fe 2+ -Cu 2+ -H 2 O 2 were mutagenic in both S. typhimurium TA1535 and E. coli WP2 uvrA. These results demonstrate that a direct-acting mutagen was formed from N-nitrosodialkylamines, with alkyl chains longer than propyl, by the oxidation in the Fe 2+ -Cu 2+ -H 2 O 2 system.

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“…a-Acetoxy nitrosamine is hydrolyzed by esterase in vivo to form a-hydroxy nitrosamine (14,15); thus, many studies have used aacetoxy nitrosamine to investigate its chemical behavior (16)(17)(18)(19)(20), bacterial mutagenicity (20), and mutagenicity towards mammalian cells (21). In 1980, the a-hydroxy nitrosamines were isolated by deoxygenation of ahydroperoxy nitrosamines (22) and their chemical properties and mutagenicity have been elucidated (23,24). The results revealed that a-hydroxy nitrosamines are involved in the metabolic activation of Nnitrosamines.…”

Section: Mechanism Of Dna Alkylation By N-nitroso Compoundsmentioning

confidence: 99%

Cross-linkable Nitrosamines with a Chloroalkyl Group as Candidates for Anticancer Lead Compounds

Ishikawa

Mochizuki

2007

Genes and Environment

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DNA alkylation and cross-linking are classical mechanisms underlying the activity of cancer chemotherapeutic agents such as procarbazine and mitomycin C, which are currently used in the clinic. Chloroethyl N-nitrosoureas is one group of anticancer cross-linking agents, and exert their biological activities by formation of DNA cross-links. Because anticancer chloroethyl N-nitrosoureas shows toxic side-eŠects due to protein carbamoylation, many eŠorts have been exercised to reduce unwanted sideeŠects by design of new drugs with low carbamoylating activity. N-Nitrosamines, another category of N-nitroso compounds, alkylate cellular nucleophiles in vivo, and might induce gene mutation and lead to carcinogenesis by DNA alkylation. Its active form is released after elimination of aldehyde; i.e. N-nitrosamines do not carbamoylate proteins. We have an interest in structure modiˆcation of alkylating nitrosamines as useful candidates for anticancer lead compounds. Three N-nitroso-N-(acetoxymethyl)-vchloroalkylamines, chloroethyl, chloropropyl and chlorobutylamines have been synthesized and their chemical and biological properties were evaluated. The chloropropyl nitrosamine showed mutagenicity in Salmonella typhimurium TA92 that is positively responsive to DNA cross-linker, and also showed interstrand cross-linking activity towards plasmid DNA assayed by agarose gel electrophoresis. Then three-ring aromatic moieties were introduced into the structure of chloropropyl nitrosamine to potentiate its binding a‹nity to DNA molecules. Although three aromatic analogs intercalated to double-stranded DNA, only acridine analog had DNA cross-linking activity. In TA92 strain, the acridine analog showed the highest mutagenicity among all nine N-nitroso compounds used in this study. These results suggest that the aromatic ring moiety confers DNA-intercalating ability to the cross-linkable chloropropyl nitrosamine; the acridine analog that forms DNA cross-links e‹ciently might be a potential new anticancer lead compound. To assess the application of cross-linkable nitrosamines as new anticancer agents, further investigations such as that on DNA adducts or on their activity towards cancer cells are required.

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Isolation and characterization of N-alkyl-N- (hydroxymethyl)nitrosamines from N-alkyl-N- (hydroperoxymethyl)nitrosamines by deoxygenation

Cited by 73 publications

References 8 publications

Quantum chemical studies of alkyldinitrogen species implicated in nitrosamine carcinogenesis

Quantum chemical studies of alkyldinitrogen species implicated in nitrosamine carcinogenesis

Oxidation Products of N-nitrosodialkylamines Generated by Fenton's Reagent in the Presence of Copper Are Direct Acting Mutagens

Cross-linkable Nitrosamines with a Chloroalkyl Group as Candidates for Anticancer Lead Compounds

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