Nitrosamides

In a 1-litre three-necked flask equipped with a thermometer, a mechanical stirrer and a dropping funnel, place 49 g. of redistilled cyclohexanone, 125 g. of p-tolylsulphonylmethylnitrosamide, 150 ml. of 95 per cent, ethanol and 10 ml. of water. The nitrosamide is largely undissolved. Adjust the height of the stirrer so that only the upper part of the solution is stirred and the precipitate moves slightly place the thermometer so that the bulb is in the liquid. Cool the mixture to about 0° in an ice - salt... 

If alcoholic potassium hydroxide is added to an ethereal solution of the methyl-nitrosamide and the mixture distilled, an ethereal solution of diazomethane is obtained in high yield ... 

Inhibition of Nitrosamine Formation. Nitrites can react with secondary amines and A/-substituted amides under the acidic conditions of the stomach to form /V-nitrosamines and A/-nitrosamides. These compounds are collectively called N-nitroso compounds. There is strong circumstantial evidence that in vivo A/-nitroso compounds production contributes to the etiology of cancer of the stomach (135,136), esophagus (136,137), and nasopharynx (136,138). Ascorbic acid consumption is negatively correlated with the incidence of these cancers, due to ascorbic acid inhibition of in vivo A/-nitroso compound formation (139). The concentration of A/-nitroso compounds formed in the stomach depends on the nitrate and nitrite intake. 

The Carbitol (monoethyl ether of diethylene glycol) was the Carbide and Carbon Chemicals Company product, which was distilled before use, b.p. 192-196°. It is a suitable solvent to render the reactants mutually soluble. Aqueous alkali with an ether solution of the nitrosamide does not yield diazomethane. 

Nitrosamide prepared as previously described, not recrystallized, is suitable for the present preparation. The solubility of the nitrosamide in ether drops sharply with temperature below 20°, more than the specified amount of ether may be required, especially if recrystallized nitrosamide is used. 

They are converted by nitrous acid into the organic acid, and in the case of substituted amides into nitrosamides,... 

Mechanisms for the thermal and photolytic decomposition of N -nitrosamides are briefly reviewed, and recent results for their decomposition by acidic and basic catalysts are summarised and discussed ... 

There is much evidence to suggest that carcinogenic N-nitros-amines are metabolised by an oxidative process to produce an alkylating agent (J f2) One potential metabolite is therefore the corresponding N-nitrosamide resulting from 2-electron oxidation at the oc-carbon atom, and, indeed, such compounds appear to induce tumours at the site of application without metabolic activation (3) It follows that the chemical properties of N-nitrosamides are relevant to the etiology of cancer ... 

N-Nitrosamides are much less stable than the parent N-nitros-amines and they can decompose by either thermal, photolytic or acid and base (nucleophilic) catalysed pathways Thermal decomposition has attracted much attention as a clean method of deamin-... 

On treatment with gaseous HBr in organic solvents, N-nitros-amides regenerate the parent amide (equation 3) in quantitative yield (7f ) This implies that N-nitrosamide formation is reversible and explains why it is beneficial to add one mole of base... 

N-nitrosamide and the solvent acidity, but generally denitrosation is more strongly acid-catalysed hence, it is a minor reaction ( <109 ) above pH 2 and the major pathway in concentrated acid ... 

The acid catalysed denitrosation of N-nitrosamides is subject to a substantial solvent deuterium isotope effect [k (H)/k (D)... 

By analogy with regular amides N-nitrosamides should... 

The tendency for N-nitrosamides to undergo hydrolysis by a nucleophilic catalysed pathway has been confirmed by studies of N-alkylnitroso acetamides (22) Results summarised in Table I for N -n-butyl-JJ -nitroso acetamide show that its decomposition is also subject to steric constraints (2,6-lutidinestrong nucleophiles (eg. imidazole, thiols) irrespective of their base strength (pK ). Further, the second order dependence on [Imidazole] is more clearly defined for the decomposit-... 

Thus, N-nitrosamides also undergo deamination (hydrolysis) by an addition-elimination pathway involving nucleophilic rather than... 

One goal of our current investigation is to show that genetically important cellular constituents can initiate the release of an alkylating agent from the N-nitrosamide. This might explain how highly reactive diazohydroxide metabolites effect the alkylation of nucleic acids within the cell nucleus. Preliminary evidence ( ) summarised in Table II shows that the decomposition of... 

The N-nitrosation of these amides was subsequently studied as a function of pH and temperature (78). There was no apparent pH maximum for the reaction, N-nitrosamide formation increasing with increasing hydrogen ion concentration. The rates of N-nitrosation decreased rapidly as the pH increased and little reaction occurred above pH 3. A unit drop in pH from 2 to I increased the rate of N-nitrosation by a factor of 5-8 times. 

Decomposition studies confirmed that N-nitrosamides are much less stable than volatile N-nitrosamines such as NPYR and NDMA (79). Thermal studies utilizing heating conditions commonly encountered in the cooking of bacon and pork roasts indicated that N nitrosomethylpropionamide (NOMP) was degraded to the extent of 74-97% compared to 3-14% for NPYR and NDMA (Table V). It was tentatively concluded that the major... 

The class of Il-nitroso compounds (l e , nitrosamines and nitrosamides) is currently considered a unique group that includes members with remarkable carcinogenic properties. Because of their potency and almost ubiquitous presence in... 

An attempt to estimate human daily impact of N nitroso compounds is shown in Table I. The apparent intake from food of preformed nitrosamines is comparatively low, at least in these surveys of a Western diet in England (3). The Intake directly to the respiratory tract from smoking could be somewhat larger. However, if the blood levels reported are confirmed as correct, then inputs of up to 700 meg per day of at least N nitrosodimethylamine (NDMA) may be calculated, based on pharmacokinetic considerations of data obtained in animals and extrapolated to man. It should be emphasized that no information is available at present on nitrosamide intake or in vivo formation, largely because of analytical limitations. 

Under appropriate condition, the peptide bond may react with aqueous nitrous acid to form a nitrosamide (32). It has been shown (33, 34, 35) in model systems that N-substituted amines can be formed by reaction between free amines and triglycerides. 

Mirvish (53,54) discovered that vitamin C could inhibit ni-trosation reactions. The purely chemical interaction of ascorbic acid with nitrite has been studied for theoretical reasons and because of its importance in the preservation of foods. This interaction has received increased attention for minimizing the presence of nitrosamines and nitrosamides in the environment, and especially in foods. We have studied the relationship in gastric carcinogenesis between high levels of nitrite, including pickling, and of vitamin C as a protective and inhibiting element. 

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