A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug.

Tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, reacts readily with nitrite in acetic acid to produce a complex product mixture. Fourteen compounds have been identified as products of this transformation when an 8-fold excess of HNO2 is used. The products, which include N-nitrosoamides, esters, alcohols, and phenylacetic acid, are rationalized as arising from a cascade of reactive diazonium ions.

Nucleoside and DNA adducts from N-nitrosotolazoline.

The reaction of N-nitrosotolazoline, the nitrosation product of a representative imidazoline receptor drug tolazoline, with DNA, deoxyguanosine (dG), or deoxyadenosine (dA) produces adducts containing the 2-phenylacetamidoethyl group. The synthesis and characterization of 2-phenylacetamidoethyl-guanine derivatives (O6-dG, O6-Gua, N2-Gua, and 7-Gua) and 2-phenylacetamidoethyladenine derivatives (1-Ade, 3-Ade, 7-Ade, and N6-Ade) are described. In addition to the use of an established UV spectral method for confirming the structure of the alkyl adenines, a new 13C NMR method for determining the N-alkylation site is presented.

N-nitrosotolazoline: decomposition studies of a typical N-nitrosoimidazoline.

N-nitrosotolazoline ( N-nitroso-2-benzylimidazoline), a N-nitrosated drug typical of N-nitrosoimidazolines, reacts readily with aqueous acid, nitrous acid, or N-acetylcysteine to produce highly electrophilic diazonium ions capable of alkylating cellular nucleophiles. The kinetics and mechanism of the acidic hydrolytic decomposition of N-nitrosotolazoline have been determined in mineral acids and buffers. The mechanism of decomposition in acidic buffer is proposed to involve the rapid reversible protonation of the imino nitrogen atom followed by slow general base-catalyzed addition of H2O to the 2-carbon of the imidazoline ring to give a tetrahedral intermediate, which is also a alpha-hydroxynitrosamine.