Nitrenium Research Articles

Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes

A set of 16 mutagenic aminoimidazo-azaarenes, including four that have been isolated from cooked foods and identified as bacterial mutagens and rodent carcinogens, was selected from a larger series previously published [Hatch et al. (1991): Environ Mol Mutagen 17:4-19] for an in-depth structure-activity study using computational methods. Structural features believed to affect mutagenic potency were tabulated. Molecular orbital energies and other electronic properties of these compounds were calculated using Huckel, semiempirical AM1, and ab initio quantum mechanical methods. Factor interrelationships were studied by multiple linear regression and canonical correlation analyses. Our goal was an improved understanding of the chemical basis of mutagenicity for this class of heterocyclic amines. The major findings were as follows: 1) mutagenic potency is related to the size of the aromatic ring system; 2) potency is enhanced by the presence and location of an N-methyl group; 3) potency is enhanced by addition of ring nitrogen atoms in pyridine, quinoline, and quinoxaline configurations; 4) potency is inversely related to the energy of the LUMO (lowest unoccupied molecular orbital) of the parent amines; 5) potency is directly, though weakly, related to the LUMO energy of the derived nitrenium ions; and 6) the calculated thermodynamic stability of the nitrenium ions (relative to the parent amine) is directly correlated with nitrenium LUMO energy and with the negative charge on the exocyclic nitrogen atom. Although this study raises several intriguing issues relating mutagenicity to chemical properties, further study will be required to determine the plausibility of the nitrenium ion as the ultimate mutagen for binding to DNA.

How Do Different Fluorine Substitution Patterns Affect the Electronic State Energies of Phenylnitrene?

Substituted phenylnitrenes, reacting out of their closed-shellsinglet (CSS) states, can serve as photoaffinity labeling reagents if they engage in bond insertion reactions.1-3 Such reactivity is similar to that exhibited by singlet phenylcarbene.4 However, the reactivity of unsubstituted CSS phenylnitrene (PhN) is dominated by unimolecular ring expansion to form didehydroazepine.4,5 Substituents on the aromatic ring are required for bimolecular insertion reactions to compete with ring expansion, e.g., polyfluorinated phenylnitrenes, which were first examined by Banks and Prakash.6,7 Platz has demonstrated that the barrier to ring expansion in 2,6-difluorophenylnitrene ((o,oF2)PhN) is increased by 3-5 kcal/mol compared to unsubstituted PhN.4,8 Platz has also shown that proper location of the fluorines on the aromatic ring is critical to this effect; 3,5difluorophenylnitrene ((m,m-F2)PhN), like PhN, undergoes ring expansion faster than it participates in insertion reactions.2-4 Elucidating the energies for different electronic states of PhN has been the goal of several experimental9,10 and theoretical11-13 studies. Theory and experiment are in good agreement on the relative ordering of the lowest energy states. The ground state is a triplet (A2), the first excited state is an open-shell singlet (A2) lying about 18 kcal/mol higher in energy, and higher still is the first CSS (1A1). No experimental number is available for the relative energy of the latter state, but reasonable quality singleand multireference configuration interaction (CISD+Q) calculations place it 31-39 kcal/mol above the triplet. The electronic configuration of this state is dominated by double occupation of the nitrogen p orbital that lies in the plane of the aromatic ring. The next higher lying CSS (2A1) is derived from double excitation of that pair of electrons out of the inplane p orbital and into the aromatic π system. Kim et al.12 have estimated the energy of this state to be about 52 kcal/mol above the triplet, but the errors associated with this calculation may be substantial (vide infra). The energy of this state bears on the ring expansion reactivity of PhN insofar as it correlates with the CSS ground state of didehydroazepine, i.e., the ring expansion is a Wagner-Meerwein shift of a C-C bond to the electron-deficient nitrogen using the empty in-plane p orbital. On the basis of this analysis, Platz has speculated that different fluorine substitution patterns may preferentially stabilize the 1A1 state and hence lead to higher activation barriers for ring expansion.4 Of course, a more complete explanation includes the recognition that there must be an avoided crossing in the state-symmetry correlation diagrams, but the crux of the argument remains a differential effect on the relative energies of the two CSS states (Figure 1). In order to address this question, we have employed density functional theory14 (DFT) to calculate15,16 the relative energies of the triplet and CSS states of PhN, (o,o-F2)PhN, (m,m-F2)PhN, and 4-fluorophenylnitrene (p-FPhN) and their corresponding didehydroazepines. To assess the quality of this level of theory, we have compared the DFT results for PhN to multireference second-order perturbation theory (CASPT2N)17,18 employing an eight-electron/eight-orbital active space and also to single-reference coupled cluster19 calculations including all single, double, and perturbative triple20 excitations (CCSD(T)). These calculations are summarized in Table 1. The gap between the A2 and 1A1 states for PhN appears to be well predicted by DFT. On the basis of the results for methylene, Roos has suggested that the CASPT2N level overstabilizes triplets relative to singlets by 3-5 kcal/mol.21 Our own calculations for various carbenes and nitrenium ions have shown similar overstabilizations of triplet states by up to 8 kcal/ mol.22 The CCSD(T) calculations also support the DFT results. Because of the size of PhN, calculations at this level were not performed using a triple-u basis. The larger stabilization of the triplet at this level of theory compared to DFT is consistent with lesser flexibility in the basis set and the observed tendency of CCSD(T) to overstabilize triplets relative to CSSs by 1-2 kcal/mol in carbenes and nitrenium ions.22 Similar levels of DFT have previously been shown to accurately predict singlet-

Reactions of Glutathione with Carcinogenic Esters of N-Arylhydroxamic Acids

The nitrenium ions 7a and 7b derived from hydrolysis of N-(sulfonatooxy)-N-acetyl-2-aminofluorene (1a) and N-(sulfonatooxy)-N-acetyl-4-aminobiphenyl (1b) are trapped by glutathione anion (GS-) with selectivity ratios, kgs−/ks, of 8200 ± 600 M-1 and 300 ± 15 M-1, respectively. Since ks is known for both of these ions under our reaction conditions, kgs− can be calculated. For 7a, kgs− is 6.3 × 108 M-1 s-1, and for 7b, kgs− is 1.8 × 109 M-1 s-1. Under physiological conditions (50−100 μM GS-) neither ion would be efficiently trapped by GS-. Some of the GSH adducts isolated in this study (4 from 1a, 11 and 12 from 1b) are not derived from nitrenium ion trapping. They arise from GS- trapping of the quinol imines 8a and 8b, which are the initial products of trapping of 7a and 7b by H2O. This reaction is very efficient at physiological GS- concentrations and could lead to significant GSH depletion in vivo. Although it has been known for some time that quinol imines such as 8a and 8b are major hydrolysis products of carcinogenic esters of N-arylhydroxylamines and N-arylhydroxamic acids, no physiological role has been previously suggested for these materials.

Acid−Base Properties of Arylnitrenium Ions

This study uses a combination of laser flash photolysis (LFP) and product analysis to show that singlet nitrenes from the irradiation of phenyl, 4-biphenylyl, and 2-fluorenyl azide can be trapped by protonation in aqueous solutions forming nitrenium ions. With phenyl azide, the phenylnitrenium ion is indicated by the formation of ring-substituted anilines in yields of up to 50% in 1 M acids. The acidity dependence furnishes the ratio kH:kexp = 1.1, where kH refers to H+-trapping of singlet phenylnitrene and kexp to ring expansion of this species. With kH expected to be 2−4 × 1010 M-1 s-1, kexp is therefore estimated as 2−4 × 1010 s-1. Protonation by solvent water also occurs, but even though the rate constant is of the order of 109 s-1, it constitutes a minor pathway in competition with the ring expansion. LFP studies in acids reveal a transient that is assigned the structure of N-protonated 4-hydroxy-2,5-cyclohexadienone imine, the intermediate formed by water addition to the para position of the phenyln...

Neoplastic transformation and DNA-binding of 4,4'-methylenebis(2-chloroaniline) in SV40-immortalized human uroepithelial cell lines.

The tumorigenic transformation of certain occupationally significant chemicals, such as N-hydroxy-4-4'-methylenebis[2-chloroaniline] (N-OH-MOCA), N-hydroxy-ortho-toluidine (N-OH-OT), 2-phenyl-1,4-benzoquinone (PBQ) and N-hydroxy-4-aminobiphenyl (N-OH-ABP) were tested in vitro using the well established SV40-immortalized human uroepithelial cell line SV-HUC.PC. SV-HUC cells were exposed in vitro to varying concentrations of N-OH-MOCA, N-OH-OT, N-OH-ABP and PBQ that caused approximately 25% and 75% cytotoxicity. The carcinogen treated cells were propagated in culture for about six weeks and subsequently injected subcutaneously into athymic nude mice. Two of the fourteen different groups of SV-HUC.PC treated with different concentrations of N-OH-MOCA, and one of the three groups exposed to N-OH-ABP, formed carcinomas in athymic nude mice. 32P-postlabeling analyses of DNA isolated from SV-HUC.PC after exposure to N-OH-MOCA revealed one major and one minor adduct. The major adduct has been identified as the N-(deoxyadenosin-3',5'-bisphospho-8-yl)-4-amino-3-chlorob enz yl alcohol (pdAp-ACBA) and the minor adduct as N-(deoxyadenosin-3',5'-bisphospho-8-yl)-4-amino-3-chlorot oluene (pdApACT). Furthermore, SV-HUC.PC cytosols catalyzed the binding of N-OH-MOCA to DNA, in the presence of acetyl-CoA, to yield similar adducts. The same adducts were also formed by chemical interaction of N-OH-MOCA with calf thymus DNA, suggesting that the aryl nitrenium ion may be the ultimate reactive species responsible for DNA binding. The tumorigenic activity of N-OH-MOCA in this highly relevant in vitro transformation model, coupled with the findings that SV-HUC.PC cells formed DNA-adducts in vitro and contained enzyme systems that activated N-OH-MOCA to reactive electrophilic species that bound to DNA, strongly suggest that MOCA could be a human bladder carcinogen. These findings are consistent with the International Agency for Research on Cancer's classification of MOCA as a probable human carcinogen.

Crystal and Electronic Structure of Stable Nitrenium Ions. A Comparison with Structurally Related Carbenes

The isolation of bis-amino-substituted carbenes of the Arduengo (3a) and Wanzlick type 4a has prompted us to look for stable nitrenium ions of the related structural type 3d+ and 4d+. Thus 5+I- (6+I-) and 18+ClO4- were isolated and structurally characterized by X-ray crystallography. Theoretical studies give insight into the different (electronic) structures and stabilities of 3a,d+, 4a,d+, and of related compounds.

Involvement of Free Nitrenium Ions, Ion Pairs, and Preassociation Trapping in the Reactions of Ester Derivatives of N-Arylhydroxylamines and N-Arylhydroxamic Acids in Aqueous Solution

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTInvolvement of Free Nitrenium Ions, Ion Pairs, and Preassociation Trapping in the Reactions of Ester Derivatives of N-Arylhydroxylamines and N-Arylhydroxamic Acids in Aqueous SolutionMichael Novak, Mary Jo Kahley, Jing Lin, Sonya A. Kennedy, and Tishia G. JamesCite this: J. Org. Chem. 1995, 60, 25, 8294–8304Publication Date (Print):December 1, 1995Publication History Published online1 May 2002Published inissue 1 December 1995https://doi.org/10.1021/jo00130a034RIGHTS & PERMISSIONSArticle Views302Altmetric-Citations56LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Get e-AlertsSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts

Mutagenicity of nitro- and amino-substituted carbazoles in Salmonella typhimurium. II. Ortho-aminonitro derivatives of 9H-carbazole

The mutagenicity of 4 ortho-aminonitrocarbazoles and 2 ortho-acetamidonitrocarbazoles was assayed in Salmonella strains TA1538, TA98, TA100, TA1537 and TA1977 and in nitroreductase and acetylase deficient strains TA98NR and TA98/1,8DNP 6, with and without S9 from phenobarbital-induced rat liver. Mutagenicity of these compounds and of their monosubstituted precursors (André et al., Mutation Res. 299 (1993) 63–73) was tentatively correlated with various molecular descriptors. The hydrophobicity appears as an important determinant of direct mutagenicity in this series of closely related nitrocarbazoles, with a general trend of increasing mutagenicity with an increase of hydrophobicity. On the contrary, the ease of nitroreduction (depicted by electrochemical reduction potential and energy of the lowest unoccupied molecular orbitals) does not appear as a major direct determinant. The ortho-amino group does not favour mutagenic potential, except for 1-nitro-2-aminocarbazole, which is the most potent direct mutagen. Mutagenicity in the presence of S9 is attributed mainly to amine metabolism. Hydrophobicity has only a limited effect on this activity, whereas an unexpected positive correlation is found with electrochemical oxidation potential. The influence of reciprocal electronic delocalization effects of nitro and amino groups, through the modulation of the ultimate mutagenic species (nitrenium ion) reactivity, is also discussed.

Myeloperoxidase as a generator of drug free radicals.

Reactive metabolites are believed to be responsible for many types of toxicity, including idiosyncratic drug reactions. Bone marrow is a frequent target of idiosyncratic reactions, and, since these reactions have characteristics that suggest involvement of the immune system, the formation of reactive metabolites by leucocytes could also play a role in the aetiology of idiosyncratic drug reactions. The major oxidation system in neutrophils and monocytes is a combination of NADPH oxidase and myeloperoxidase. This system oxidizes primary arylamines, such as sulphonamides, to reactive metabolites and these drugs are also associated with a high incidence of agranulocytosis, generalized idiosyncratic reactions and/ or drug-induced lupus. Clozapine is oxidized by this system to a relatively stable nitrenium ion; clozapine is also associated with a high incidence of agranulocytosis. Arylamines that have an oxygen or nitrogen in the para position, such as amodiaquine, vesnarinone and 5-aminosalicylic acid, are oxidized to quinone-like reactive intermediates. Aminopyrine is oxidized to a very reactive dication. Such reactive metabolites could also inhibit neutrophil function and mediate some of the therapeutic effects of these drugs: for example, the use of dapsone for dermatitis herpetiformis and the use of 5-aminosalicylic acid for inflammatory bowel disease.

ChemInform Abstract: Photogenerated Arylnitrenium Ions: Reactions of N‐tert‐Butyl (2‐Acetyl‐ 4‐substituted)phenyl Nitrenium Ions with Alcohols and Water Studied by Laser Flash Photolysis.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Photogenerated Arylnitrenium Ions: Reactions of N-tert-Butyl(4-substituted 2-acetylphenyl)nitrenium Ions with Alcohols and Water Studied by Laser Flash Photolysis

Photogenerated Arylnitrenium Ions: Reactions of N-tert-Butyl(4-substituted 2-acetylphenyl)nitrenium Ions with Alcohols and Water Studied by Laser Flash Photolysis

Selective Trapping of N-Acetyl-N-(4-biphenylyl)nitrenium and N-Acetyl-N-(2-fluorenyl)nitrenium Ions by 2'-Deoxyguanosine in Aqueous Solution

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSelective Trapping of N-Acetyl-N-(4-biphenylyl)nitrenium and N-Acetyl-N-(2-fluorenyl)nitrenium Ions by 2'-Deoxyguanosine in Aqueous SolutionMichael Novak and Sonya A. KennedyCite this: J. Am. Chem. Soc. 1995, 117, 1, 574–575Publication Date (Print):January 1, 1995Publication History Published online1 May 2002Published inissue 1 January 1995https://doi.org/10.1021/ja00106a083RIGHTS & PERMISSIONSArticle Views239Altmetric-Citations82LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (248 KB) Get e-Alerts Get e-Alerts

Relative preferences of carcinogenic aromatic nitrenium ions for adduct formation with different DNA base sites: Theoretical elucidations

The ultimate carcinogenic form of aromatic amines, the nitrenium ions, interact with DNA bases in order to exert their carcinogenic effects.

Reactions of 8H-Furo[3,4-d]dibenz[b,f]azepine and 9H-Tribenz[b,d,f,]azepine with t-Butyl Hypochlorite and Silver Trifluoroacetate. Attempts to Form a Long-lived Aromatic Nitrenium Ion

Reactions of 8H-Furo[3,4-d]dibenz[b,f]azepine and 9H-Tribenz[b,d,f,]azepine with t-Butyl Hypochlorite and Silver Trifluoroacetate. Attempts to Form a Long-lived Aromatic Nitrenium Ion

Nitroreduction of 1- and 3-nitro-7,8,9,10-tetrahydrobenzo[a]pyrene and 1-nitrobenzo[a]pyrene resulting in formation of N2-deoxyguanosinyl adducts through long-range migration.

We recently reported that the reaction of N-hydroxy-3-aminobenzo[a] pyrene with calf thymus DNA produced 6-(deoxyguanosin-N2-yl)-3-aminobenzo[a]pyrene as the predominant adduct. The deoxyguanosinyl group of this adduct resides at the C6 position, which is remote from the reaction site, the nitrenium ion. It is significant to determine if formation of this type of DNA adduct is general and whether or not adduct formation is due to an increase in the stabilization of the nitrenium ion by increasing aromaticity. Thus, reduction of 1-nitro-7,8,9,10-tetrahydrobenzo[a]pyrene, 3-nitro-7,8,9,10-tetrahydrobenzo[a]pyrene, and 1-nitrobenzo[a]pyrene, both chemically and enzymatically, followed by reaction with calf thymus DNA was investigated. DNA was isolated and enzymatically digested, and the resulting modified nucleosides were separated by HPLC. Upon spectral analyses by mass and proton nuclear magnetic resonance spectroscopy, 6-(deoxyguanosin-N2-yl)-1-amino-7,8,9,10-tetrahydrobenzo[a] pyrene, 6-(deoxyguanosin-N2-yl)-3-amino-7,8,9,10-tetrahydrobenzo[a]pyrene, and 6-(deoxyguanosin-N2-yl)-1-aminobenzo[a]pyrene were identified, respectively. The same DNA adducts were formed from xanthine oxidase-mediated reductive metabolism of 1-nitro-7,8,9,10-tetrahydrobenzo[a]pyrene, 3-nitro-7,8,9,10-tetrahydrobenzo[a]pyrene, and 1-nitrobenzo[a]pyrene in the presence of calf thymus DNA. Thee results indicate that formation of N2-deoxyguanosinyl adducts of this type is common and that increasing the aromaticity by increasing the number of aromatic rings is not a decisive factor in directing their formation.

Substituent effects on the genotoxicity of 4-nitrostilbene derivatives

4-Nitrostilbene and twelve of its derivatives (eleven E-stilbenes and two Z-stilbenes) were examined for possible quantitative structure-activity relationships of their in vitro and in vivo genotoxicity. Relative mutagenicity was studied with and without S9 activation in Salmonella strains TA98 and TA100, as well as in the nitroreductase deficient strains TA98/NR and TA100/NR. Chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of the nitrostilbenes were observed as an indicator of in vivo genotoxicity. All of the compounds were active in TA98 and TA100 without S9 activation, with the exception of 4-amino-4′-nitrostilbene in TA100. Mutagenic activity was greatly reduced or eliminated in the NR strains, which is consistent with metabolic activation of the compounds by bacterial reductase. The presence of S9 lowered the activity of most of the nitrostilbenes presumedly by enzymatic detoxication. Hammet values of substituents, partition coefficients and frontier orbital energies ( E LUMO and E HOMO) were studied for correlations with mutagenicity of the eleven E-stilbenes. Correlations could be established between mutagenicity in TA98 without S9 activation and the Hammet values. The same mutagenicity could also be correlated to E LUMO. Rationales for these correlations include the concept that electron-withdrawing groups which lower E LUMO should facilitate the reduction of the nitro group, leading to the proximate mutagen hydroxylamine. The correlations are also explained by the concept that electron-withdrawing groups should help stabilize the hydroxylamine intermediate and make the ultimate mutagenic species, the nitrenium ions, more reactive toward DNA. The relationship between mutagenicity and electronic effects of substituent groups found in vitro could not be extended to the in vivo results. However, except for the dinitrostilbenes, where insolubility prevented their testing, all the nitrostilbenes produced a statistically significant increase in chromosomal aberrations compared to the negative solvent control.

Photogenerated nitrenium ions: Singlet and triplet state reactions of tert-butyl-(2-acetyl-4-methyl)phenyl nitrenium ion

Photolysis of an anthranilium salt, 5-methyl-3-N- tert-butyl-2,1-benzisoxazolium tetrafluoroborate ( 1a) gives the title nitrenium ion 2a. Under direct photolysis of 1a, in the presence of nucleophiles (i.e. ROH), quinone imine ethers such as ( 6) are the major product. Triplet sensitized irradiation gives both 6 and the parent amine 5.

ChemInform Abstract: Cyclization with Nitrenium Ions Generated from N‐Methoxy‐, or N‐ Allyloxy‐N‐chloroamides with Anhydrous Zinc Acetate. Synthesis of N‐ Hydroxy‐ and N‐Methoxynitrogen Heterocyclic Compounds.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cyclization with Nitrenium Ions Generated from N-Methoxy- or N-Allyloxy-N-chloroamides with Anhydrous Zinc Acetate. Synthesys of N-Hydroxy- and N-Methoxynitrogen Heterocyclic Compounds

Electrophilic intramolecular aromatic substitution with an N-methoxy- or an N-allyloxy-acylnitrenium ion, generated by treatment of an N-methoxy- or an N-allyloxy-N-chloroamide with anhydrous zinc acetate in nitromethane, leads to formation of a nitrogen heterocyclic compound bearing an N-methoxy- or N-allyloxy group. The latter is readily converted to the corresponding N-hydroxy compound by palladium-catalyzed removal of the allyl group

Polycondensed nitrogen heterocycles. Part 25. Aminopyrrolo[1,2‐f]‐phenanthridines by decomposition of 2‐(3‐azidophenyl)‐1‐arylpyrroles

AbstractAcid catalyzed decomposition of the azido derivatives 4a‐c gave rise to amino‐hydroxy‐phenylpyrroles of type 7 and 8 upon hydrolysis of the intermediate aryl nitrenium ions, together with the hydrogen abstraction compounds of type 3. The aminopyrrolo[1,2‐f]phenanthridines 10, 11, and 12 were obtained by treatment with TFMSA of the azide 4d in which the ring being attacked was made more nucleophilic by the introduction of the methoxy group.