Nitrosamine cyclic

Symmetrical dialkyl-nitrosamines Methyl alkyl nitrosamines Cyclic nitrosamines Aryl-alkyl and diaryl nitrosamines... 

Cyclic nitrosamines are among the most potent and environmentally significant nitrosamine carcinogens. Like the acyclic nitrosamines, metabolism is necessary for their carcinogenicity. Elucidation of the specific metabolic pathways of cyclic nitrosamine activation and detoxification is a challenging problem, and considerable progress has been achieved in recent years. In this chapter, we will review metabolic studies on N-nitrosopyrrolidine (NPYR), N -nitrosonornicotine (NNN), N-nitrosopiperidine (NPIP), N-nitrosohexamethyleneimine (NHEX), N-nitrosomorpholine (NMOR),... 

These studies on NPYR are typical of the state of the art in cyclic nitrosamine metabolism ai d activation. The major metabolic pathways have been rather well characterized, but data on the relationship of these pathways to carcinogenesis are limited. This is especially true of the organospecific effects of NPYR and the other cyclic nitrosamines. For example, the main target organs for NPYR in the Syrian golden hamster are the trachea and nasal cavity rather than the liver. This is in spite... 

In contrast, little is known about the DNA adducts formed from cyclic nitrosamines. Early studies indicated methylation of DNA by certain cyclic nitrosamines but these were not confirmed (25, 71, 72). Adducts from NPYR and NMOR have been detected but remain mostly uncharacterized (25, 61). The nature of the... 

Our studies on cyclic nitrosamine metabolism are supported by NCI Grants CA-21393, CA23901, and CA12376. This is paper Number 34 in A Study of Chemical Carcinogenesis. ... 

Figure 3, Structures of oxygen-containing cyclic nitrosamines nitrosomorpholine, 2-methylnitrosomorpholine, 2,6-dimethylnitrosomorpholine, nitroso-1,3-oxazoli-dine, 5-methylnitroso-l,3-oxazolidine, 2-methylnitroso-l,3-oxazolidine, nitrosotet-...

N-Nitrosamines are formed during processing and smoking of tobacco products. Proteins, agricultural chemicals and alkaloids in tobacco products serve as major precursors for volatile, nonvolatile, and tobacco-specific nitrosamines (Figure 1). In this review we will summarize the progress achieved in respect to tobacco nitrosamines since the last ACS symposium in Boston in June of 1978 (J ). Additional papers will review the metabolism of cyclic N-nitrosamines, including that of N -nitrosonornicotine 1) and the correlation between tobacco and alcohol consumption and cancer of the upper alimentary tract (J ). 

As a continuation of the interest in the electronic circular dichroism (ECD) of the chiral nitrosamines, the ECD of the /V-nitroso derivatives of chiral 4-, 5- and 6-membered cyclic... 

Barriers to rotation of nitrosamines in which the amino part is embedded in a cyclic system seem generally to be smaller. However, Harris and associates (82) reported that the barrier of /V-nitroso-2,2,5,5-tetramethylpyrrolidine (43) was over 22.6 kcal/mol. This must be higher than the barrier required for isolation of rotamers at room temperature, and is even higher than that in /V-nitroso-2,2,6,6-tetramethylpiperidine (44). Harris and Pryce-Jones attribute the high barrier of 43 relative to 44 to the more stable ground state of the former. If the pyrrolidine derivative is properly substituted, the atropisomers are expected to be isolable at room temperature. 

The nitrolysis of nitrosamines has been relatively unexplored because of the high toxicity of such substrates. Atkins and Willer have prepared a number of cyclic 1,3-dinitrosamines... 

The reaction of hexamine dinitrate (241) with 98% nitric acid at —30°C, followed by quenching with aqueous sodium nitrate, yields the nitrosamine (244). When the same reaction is cautiously quenched with ethanol the ethoxyether (245) is obtained. Treatment of the ethoxyether (245) with cold absolute nitric acid yields the bicyclic ether (246). ° Treatment of any of the cyclic nitramines (242)-(246) with nitric acid and ammonium nitrate in acetic anhydride yields RDX. ° Hexamine dinitrate is often used in low temperature nitrolysis experiments in order to avoid the initial exotherm observed on addition of hexamine to nitric acid. 

The interesting "dimerization of lithiated N-nitrosamines to cyclic tetrazene N-oxides has been described (U8) and provides another route to the novel cyclic tetrazenes (U9, 0) A radical path has been suggested for this reaction [Scheme h] ( ). 

Figure 6. Correlation of the biological activity and the availability of a syn-axial-proton in cyclic six-membered nitrosamines...

The formation of NNN, NNK, and NNA from nicotine probably involved the intermediacy of cyclic iminium salts, as shown in Figure 5 (28). These salts can undergo hydrolysis to the free amines which are nitrosated, or at near neutral pH, can be directly nitrosated to give nitrosamines. The formation of nitrosamines from iminium salts under neutral conditions has been demonstrated in at least two studies and is of interest because iminium salts are known to be intermediates in the mammalian metabolism of nicotine (26,29,30,31). The possibility that tobacco bacteria could nitrosate nicotine via this pathway is currently under investigation. 

Syndex, C.M./ Farelly, J.G. and Lijinsky, W., Metabolism of Three Cyclic Nitrosamines in Sprague Dawley Rats , Cancer Res, 1 77, 37, 3530--3532. 

In summary, it appears that the differences in carcinogenic potency for both cyclic and acyclic N-nitrosodialkylamines are real and systematic, and that the potencies of environmental nitrosamines should be considered in assessing the relative hazards associated with these compounds. In addition, it can be shown that the carcinogenicity of nitrosamines can be associated... 

Dahl, A.R. (1985) Mutagenicity of some dialkylnitrosamines, cyclic nitrosamines and N,N-di-ethanolnitrosamine in Salmonella typhimurium with rat and rabbit nasal, lung and liver S9 homogenates. Mw/at. Res., 158,141-147... 

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