N-Nitrosamides

Critical position/factor Effect on carcinogenic potential Rationale 

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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... 

N-Nitrosamines have been shown to be inhibitors of cysteine-containing enzymes. For example, dephostatin and other N-methyl-N-nitrosoanilines (1) were found to be inhibitors of the protein tyrosin phosphatases, papain and caspase [90,91]. Inhibition results from the S-nitrosation of the critical cysteine residues in the active sites of the enzymes by the nitrosamines. Compounds 6 and 7 have been found to inhibit thrombus formation in arterioles and venules of rats [92], while N-nitrosamide 9 exhibited vasodilation and mutagenicity as a result of NO release [93]. 

Table 14.13 Critical structural feature which can affect the carcinogenicity of N-nitrosamides.

Broadly, NOC are divided into two groups (a) /V-nitrosamines and (b) N-nitrosamides. In jV-nitrosamines, the two remaining substituent groups on the >N—N=0 atom can be either alkyl or aryl, or they can form the part of a heterocyclic ring (as in N-nitrosopyrrolidine). On the other hand, in N-nitrosamides, more correctly called N-acyl-N-nitroso compounds, one of these... 

MS techniques, mainly because of its ease of operation, the commercial availability of advanced instrumentation, and the high resolving power of capillary column GC that allows one to carry out specific high-resolution measurement at extremely low levels. The GC-MS techniques are, however, not applicable to all compounds, especially the thermolabile compounds, such as N-nitrosamides, or the nonvolatile NOC. Furthermore, direct HPLC-MS analysis of nonvolatile NOC eliminates the need for derivatization. 

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