A Diazonium Ion Cascade from the Nitrosation of Tolazoline, An Imidazoline-Containing Drug

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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. Rapid decomposition of this species gives rise to the diazonium from which the products are derived by nucleophilic attack, elimination, and rearrangement. The proposed mechanism is supported by the observations of general acid catalysis, a negligible deuterium solvent kinetic isotope effect ( kH/kD = 1.15) and delta S = -34 eu. In phosphate buffer at 30 degrees C, the half-lives of N-nitrosotolazoline range from 5 min at pH 3.5 to 4 h at pH 6. The main reaction product of the hydrolytic decomposition is N-(2-hydroxyethyl)phenylacetamide. This and other products are consistent with the formation of a reactive diazonium ion intermediate. N-nitrosotolazoline nitrosates 50 times more rapidly than tolazoline and results in a set of products derived from reactive diazonium ions but different from those produced from the hydrolytic decomposition of the substrate. N-acetylcysteine increases the decomposition rate of N-nitrosotolazoline by 25 times at pH 7 and results in both N-denitrosation and induced decomposition to produce electrophiles. These data suggest that N-nitrosotolazoline shares the chemical properties of many known direct-acting mutagens and carcinogens.

“…Yield, 70%; mp 59-60 °C. 1 H NMR: δ 7.27 (m, 5 H), 6.57 (b, 1 H), 3.76 (b, 1 H), 3.56 (t, J ) 5.3, Hz, 2 H), 3.50 (s, 2H), 3.29 (t, J ) 5.3 Hz, 2 H). 13 C NMR: δ 172.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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N-Nitrosotolazoline: Decomposition Studies of a Typical N-Nitrosoimidazoline

Loeppky

Shi

2008

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“…46,88,89 An illustrative example of the chemical complexity characterizing drug nitrosation is given by the reaction of tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, with nitrite in acetic acid. 90 The products obtained with an 8-fold excess of HNO 2 include N-nitrosoamides, esters, alcohols, and phenylacetic acid, and can be rationalized as arising from a cascade of reactive diazonium ions (Scheme 12). Nitrosation of 2-hydroxyethylpiperidine in acidic media proceeds via an initial fast attack at the OH group to an alkyl nitrite in the protonated amine.…”

Section: Reviewmentioning

confidence: 99%

Secondary Targets of Nitrite-Derived Reactive Nitrogen Species: Nitrosation/Nitration Pathways, Antioxidant Defense Mechanisms and Toxicological Implications

d’Ischia

Napolitano

Manini

et al. 2011

Nitrite, the primary metabolite of nitric oxide (NO) and a widely diffused component of human diet, plays distinct and increasingly appreciated roles in human physiology. However, when exposed to acidic environments, typically in the stomach, or under oxidative stress conditions, it may be converted to a range of reactive nitrogen species (RNS) which in turn can target a variety of biomolecules. Typical consequences of toxicological relevance include protein modification, DNA base deamination and the formation of N-nitrosamines, among the most potent mutagenic and carcinogenic compounds for humans. Besides primary biomolecules, nitrite can cause structural modifications to a variety of endogenous and exogenous organic compounds, ranging from polyunsaturated fatty acids to estrogens, tocopherol, catecholamines, furans, retinoids, dietary phenols, and a range of xenobiotics. The study of the interactions between nitrite and key food components, including phenolic antioxidants, has therefore emerged as an area of great promise for delineating innovative strategies in cancer chemoprevention. Depending on substrates and conditions, diverse reaction pathways may compete to determine product features and distribution patterns. These include nitrosation and nitration but also oxidation, via electron transfer to nitrosonium ion or nitrogen dioxide. This contribution aims to provide an overview of the main classes of compounds that can be targeted by nitrite and to discuss at chemical levels the possible reaction mechanisms under conditions that model those occurring in the stomach. The toxicological implications of the nitrite-modified molecules are finally addressed, and a rational chemical approach to the design of potent antinitrosing agents is illustrated.

“…Thus, several controlled intervention and cohort studies followed (Figure A). ,,− For example, higher NOC levels were measured in stool samples from people with a high-meat diet compared to individuals with a low-meat or vegetarian diet, ,, particularly if red or processed meat was consumed. , Heme iron was found to stimulate endogenous NOC production. , Additionally, NOC formation upon consumption of meat was ascribed largely to the use of nitrate and nitrite as food preservatives and the reaction of nitrites with amines in the meat or in the human body (Figure B). These processes can be promoted by low pH ,− or catalyzed by gut microbial enzymes at neutral pH . Nitrite-dependent nitrosation also occurs in mammalian cells owing to the endogenous production of nitric oxide by nitric oxide synthase. ,, Thus, the mutagenic effects of NOC exposure, initiated by the formation of NOC-induced DNA adducts, are viewed as a likely molecular initiating event in colorectal carcinogenesis.…”

Section: Red Meat Consumption and O 6-cmg Occurrencementioning

confidence: 99%

A Chemical Link between Meat Consumption and Colorectal Cancer Development?

Aloisi

Sandell

Sturla

2021

O 6-carboxymethylguanine (O 6-CMG) is a mutagenic DNA adduct that forms at increased levels when people eat meat. It has been studied as a potential initiating event in colorectal carcinogenesis. It can arise from alkylation of guanine in DNA by electrophilic degradation products of N-nitroso compounds. There is significant data regarding biochemical and cellular process, including DNA repair and translesion DNA synthesis that control O 6-CMG accumulation, persistence, and mutagenicity. Mutation spectra arising from the adduct closely resemble common mutations in colorectal cancer; however, gaps remain in understanding the biochemical processes that regulate how and where the damage persists in the genome. Addressing such questions relies on advances in chemistry such as synthesis approaches and bioanalytical methods. Results of research in this area help advance our understanding of the toxicological relevance of O 6-CMG-modified DNA. Further attention should focus on understanding how a combination of genetic and environmental factors control its biological persistence and how this information can be used as a basis of biomoniotoring and prevention efforts to help mitigate colon cancer risk.