N-Nitrosamides

Nitrosamides are chemical compounds that contain the chemical structure R¹C(=X)N(–R²)–N=O, that is, a nitroso group bonded to the nitrogen of an amide or similar functional group.^[1] Specific classes include the N-nitrosamides, N-nitrosoureas, N-nitrosoguanidines, and N-nitrosocarbamates. Nitrosamides are usually chemically reactive, metabolically unstable,^[1] and often carcinogenic; however, in contrast to the N-nitrosamines, N-nitrosamides are not generally contaminants found in food.^[1]

Basic structure with blue emphasized functional group	N-Nitrosamide derivates with blue emphasized functional group
N-Nitrosamides	N-Nitrosocarbamates N-Nitrosoureas N-Nitrosoguanidine
R1-R3 are hydrogen atoms or organic residues

Use

Various chloroethylnitrosoureas (such as N, N'-bis (2-chloroethyl)nitrosourea, BCNU) have obtained a medical use in the field of malignant tumors.^[2] It is hypothesized that the efficacy against cancer cells is based on the alkylability of guanine cytosine centers in the sequences of the genetic material, especially the oncogenes.^[2]

Synthesis

N-Nitrosamides can be prepared starting from N-monosubstituted carboxamides and the nitrosyl cation (which results from the nitrous cation in the presence of strong acids from the nitrous acid), here exemplified for N-methylacetamide (1).^[3][4] The carboxamide reacts in a nucleophilic attack at the nitrosyl cation. After the elimination of a proton, an N-nitrosamide (2) is formed from the resulting cation:

Synthese eines N-Nitrosamids ausgehend von N-Methylacetamid

Toxicity

The genotoxic effect of the N-nitroso compounds can be attributed to the formation of reactive electrophilic species in the metabolism.^[5] The spontaneous decomposition of N-nitroso-ureas in the aqueous medium of the metabolism, here for example of 1-methylnitrosourea (3), produces diazonium or carbenium ions, respectively.^[5] The decomposition occurs into isocyanic acid and methyldiazohydroxide. The rearrangement to the diazonium ion and the subsequent elimination of nitrogen results in a carbenium ion (4), which can alkylate nucleophilic intersections of the DNA.^[5]

Zerfall eines N-Nitrosoharnstoffs zu einem alkylierenden Intermediat

In the organism, the decomposition of N-nitroso ureas with a higher degree of substitution can proceed. An alternative possible formation of diazonium and carbenium ions is through the enzymatic reaction of nitrosamines.^[5]

Typical accompanying symptoms during the medical cancer treatment via N-nitroso ureas are the impairment of bone marrow (damage of the stem cell compartment), lymphatic tissue and the gastrointestinal tract.^[5]