Some biochemical aspects of N-nitroso compounds

Digenis, George A.; Issidorides, Costas H.

doi:10.1016/0045-2068(79)90041-5

Cited by 42 publications

(24 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…but is not the case for cimetidine and etintidine, and may well not be the case for other aniide, urea. or cyanoguanidine type conipounds (6,12). The pH range for testing should be extended down to I .…”

Section: Discussionmentioning

confidence: 99%

“…and the possibility tor levels of nitrosating species and total extractable gastric N-nitroso compounds to rise ~~n d e r conditions of lowered gastric acidity (7,8). Speculation continues in spite of the findings that long-term studies of cimetidine in rats and dogs have revealed no signs of carcinogenesis (9), in vivo formation of N-nitrosocimetidine has not been reported, and there is no direct evidence to associate the development of cancer in man with exposure to N-nitroso compounds (6).…”

mentioning

confidence: 99%

“…3). the presence of nitrosating species in the ston~ach (6). and the possibility tor levels of nitrosating species and total extractable gastric N-nitroso compounds to rise ~~n d e r conditions of lowered gastric acidity (7,8).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Comparative nitrosation of etintidine and cimetidine

Montzka¹,

Juby²,

Matiskella³

et al. 1983

Can. J. Chem.

View full text Add to dashboard Cite

Etintidine (4), a new histamine H2-receptor antagonist, was compared with cimetidine (1) for susceptibility to in vitro nitrosation at pH 1 and pH 3. Each agent formed two mono-N-nitrosoguanidine derivatives: N-cyano-N′-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl}-N″-nitroso-N″-(2-propynyl)guanidine (5) and N-cyano-N′-{2-[5-methyl-1H-imidazol-4-yl)methylthio]ethyl}- N′-nitroso-N″-(2-propynyl)guanidine (6) from etintidine and N-cyano-N′-methyl-N″-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl}- N′-nitrosoguanidinc (2) and N-cyano-N′-methyl-N"-{2-[(5-methyl-1H-imidazol-4-yl)methyl-thio]ethyl}-N′-nitrosoguanidine (11) from cimetidine. The N-nitroso derivative 5 from etintidine cyclized to 2-cyanoimino-3-{2-((5-methyl-1H-imidazol-4-yl)methylthio]ethyl}-N″-methylene-1-nitroso-imidazoline (7) at neutral or basic pH's. Both agents were nitrosated less at pH 3 than at pH 1, and at both pH's nitrosation of etintidine was considerably less than that of cimetidine. At pH 1, with a nitrite concentration about 150–500 times that expected in fasting human gastric juice, formation of 5 and 6 from etintidine was barely detectable (each < 0.5%). Comments are made on the standard WHO conditions for investigating nitrosation of drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Comparative nitrosation of etintidine and cimetidine

Montzka¹,

Juby²,

Matiskella³

et al. 1983

Can. J. Chem.

View full text Add to dashboard Cite

show abstract

“…Such N-nitroso compounds are divided into two groups: N-nitrosamines and N-nitrosamides. In general, Nnitrosamines such as N-nitrosodialkylamines need to be 2 Satoko Ishikawa and Masataka Mochizuki metabolized in vivo by cytochromes P450 to attain biological activity (8); by contrast, N-nitrosamides such as N-nitroso-N-alkylureas do not need metabolic conversion and spontaneously degrade to alkanediazohydroxide (9) (Fig. 1).…”

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

View full text Add to dashboard Cite

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.

show abstract

“…= 10 min), we believed it would and 3-(4-methylcyclohe~y1)-l-(2-chloroe~hyl)-~-~i~ro~ourea be more convenient to study the decomposition of these BCNU ( M~C C N U ) are used to treat patients with malignant brain analogs into 2-haloethyldiazonium hydroxide and 2-haloethyltumors, including brain gliomas (1)(2)(3)(4). Even after numerous isocyanate, and try to correlate the results with the decomstudies, however, the phamacokinetics and mode of action of position of BCNU into 2-chloroethyldiazonium hydroxide and these drugs remain unknown (5)(6)(7). The distribution of these 2-chloroethylisocyanate (12,13).…”

Section: Because Of the Longer Half-life Of Fluorine-18 (Trlr = 110mentioning

confidence: 99%

Synthesis of ¹⁸F-labelled 2-fluoroethyl-nitrosoureas

Farrokhzad¹,

Dikšić²,

Yamamoto³

et al. 1984

Can. J. Chem.

View full text Add to dashboard Cite

18F-labelled 1,3-bis-(2-fluoroethyl) nitrosourea (18F-BFNU) (9) and 1-(2-chloroethyl)-3-(2-fluoroethyl) nitrosourea (18F-CFNU) (isomeric mixture, 11,12) were synthesized by nucleophilic attack of 18F-labelled tetra-n-butylammonium fluoride on the aziridine ring of 1,3-substituted ureas. Diethyleneurea (DEU) (5), 1-(2-fluoroethyl)-3-ethyleneurea (FEU) (7), and 1-(2-chloroethyl)-3-ethyleneurea (CEU) (14) were used as starting materials in the synthesis. Nitrosation of 18F-labelled 1,3-bis-(2-fluoroethyl) urea (18F-BFU) (6) produced 18F-BFNU with a radiochemical yield of 5–10%. Nitrosation of 18F-labelled 1-(2-chloroethyl)-3-(2-fluoroethyl) urea (18F-CFU) (15) gave 18F-CFNU as a mixture of two isomers. Geometrical isomers of CFNU were separated by hplc, and the radiochemical yield of the two isomers ranged from 8% to 15%, with a radiochemical purity exceeding 96%. Syntheses, which took about 60 min, yielded products with specific activity of 680 mCi/mmol when n-Bu4N+F− was used, or 300 mCi/mmol when HF was used to complete the opening of the aziridine ring.

show abstract

Some biochemical aspects of N-nitroso compounds

Cited by 42 publications

References 119 publications

Comparative nitrosation of etintidine and cimetidine

Comparative nitrosation of etintidine and cimetidine

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

Synthesis of ¹⁸F-labelled 2-fluoroethyl-nitrosoureas

Contact Info

Product

Resources

About

Some biochemical aspects of N-nitroso compounds

Cited by 42 publications

References 119 publications

Comparative nitrosation of etintidine and cimetidine

Comparative nitrosation of etintidine and cimetidine

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

Synthesis of 18F-labelled 2-fluoroethyl-nitrosoureas

Contact Info

Product

Resources

About

Synthesis of ¹⁸F-labelled 2-fluoroethyl-nitrosoureas