Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 26
Filter
Add more filters










Publication year range
1.
Sci Rep ; 13(1): 15713, 2023 09 21.
Article in English | MEDLINE | ID: mdl-37735226

ABSTRACT

Nitroso-compounds are potentially mutagenic and carcinogenic compounds due to their ability to alkylate DNA bases. One of the most common sources of human exposure to nitroso-compounds is their formation in the acidic environment of the stomach by the reaction between electron-rich molecules present in the lumen and sodium nitrite ingested in the diet. To date, the formation of nitroso-compounds by the reaction of nitrite with food components has been investigated in depth, but little attention has been paid to substances secreted in the stomach, such as dopamine or serotonin, whose reaction products with nitrite have proven mutagenic properties. In this article, we present a kinetic study with UV-visible spectroscopy of the nitrosation reactions of both molecules, as well as of L-tyrosine, the amino-acid precursor of dopamine. We determined the kinetic parameters and reaction mechanisms for the reactions, studying the influence of the reactants concentration, pH, temperature, and ionic strength on the reaction rate. In all cases, the favoured reaction product was a stable nitroso-compound. Serotonin, the molecule whose product was the most mutagenic, underwent two consecutive nitrosation reactions. These findings suggest that additional biological research is needed to understand how this reaction alters the function of these neurotransmitters as well as the potentially toxic effects they may have once nitrosated.


Subject(s)
Dopamine , Sodium Nitrite , Humans , Serotonin , Stomach , Nitroso Compounds , Neurotransmitter Agents
2.
Food Chem ; 216: 60-5, 2017 Feb 01.
Article in English | MEDLINE | ID: mdl-27596392

ABSTRACT

Tyramine is a biogenic compound derived from the decarboxylation of the amino acid tyrosine, and is therefore present at important concentrations in a broad range of raw and fermented foods. Owing to its chemical properties, tyramine can react with nitrite, a common food additive, in the acidic medium of stomach to form N- and C-nitroso compounds. Since toxicology studies have shown that the product of C-nitrosation of tyramine is mutagenic, in the present article tyramine nitrosation mechanisms have been characterized in order to discern which of them are favoured under conditions similar to those in the human stomach lumen. To determine the kinetic course of nitrosation reactions, a systematic study of the nitrosation of ethylbenzene, phenethylamine, and tyramine was carried out, using UV-visible absorption spectroscopy. The results show that, under conditions mimicking those of the stomach lumen, the most favoured reaction in tyramine is C-nitrosation, which generates mutagenic products.


Subject(s)
Mutagens/chemistry , Tyramine/chemistry , Benzene Derivatives/chemistry , Humans , Models, Theoretical , Nitrites/chemistry , Nitrosation , Nitroso Compounds/chemistry , Phenethylamines/chemistry , Stomach/drug effects
3.
Chem Res Toxicol ; 27(10): 1853-9, 2014 Oct 20.
Article in English | MEDLINE | ID: mdl-25222830

ABSTRACT

The chemical reactivity of styrene-7,8-oxide (SO), an alkylating agent with high affinity for the guanine­N7 position and a probable carcinogen for humans, with 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases, was investigated kinetically in water/dioxane media. UV­vis spectrophotometry and ultrafast liquid chromatography were used to monitor the reactions involved. It was found that in the alkylation process four reactions occur simultaneously: (a) the formation of a ß-NBP­SO adduct through an SN2 mechanism; (b) the acid-catalyzed formation of the stable α-NBP­SO adduct through an SN2' mechanism; (c) the base-catalyzed hydrolysis of the ß-adduct, and (d) the acid-catalyzed hydrolysis of SO. At 37.5 °C and pH = 7.0 (in 7:3 water/dioxane medium), the values of the respective reaction rate constants were as follows: kalkß = (2.1 ± 0.3) × 10­4 M­1 s­1, kalkα = (1.0 ± 0.1) × 10­4 M­1 s­1, khydAD = (3.06 ± 0.09) × 10­6 s­1, and khyd = (4.2 ± 0.9) × 10­6 s­1. These values show that, in order to determine the alkylating potential of SO, none of the four reactions involved can be neglected. Temperature and pH were found to exert a strong influence on the values of some parameters that may be useful to investigate possible chemicobiological correlations (e.g., in the pH 5.81­7.69 range, the fraction of total adducts formed increased from 24% to 90% of the initial SO, whereas the adduct lifetime of the unstable ß-adduct, which gives an idea of the permanence of the adduct over time, decreased from 32358 to 13313 min). A consequence of these results is that the conclusions drawn in studies addressing alkylation reactions at temperatures and/or pH far from those of biological conditions should be considered with some reserve.


Subject(s)
Alkylating Agents/chemistry , Epoxy Compounds/chemistry , Pyridines/chemistry , Alkylation , Catalysis , Dioxanes/chemistry , Hydrogen-Ion Concentration , Kinetics , Temperature , Water/chemistry
4.
J Org Chem ; 78(14): 6880-9, 2013 Jul 19.
Article in English | MEDLINE | ID: mdl-23731203

ABSTRACT

The acid-catalyzed hydrolysis of linear esters and lactones was studied using a hybrid supermolecule-polarizable continuum model (PCM) approach including up to six water molecules. The compounds studied included two linear esters, four ß-lactones, two γ-lactones, and one δ-lactone: ethyl acetate, methyl formate, ß-propiolactone, ß-butyrolactone, ß-isovalerolactone, diketene (4-methyleneoxetan-2-one), γ-butyrolactone, 2(5H)-furanone, and δ-valerolactone. The theoretical results are in good quantitative agreement with the experimental measurements reported in the literature and also in excellent qualitative agreement with long-held views regarding the nature of the hydrolysis mechanisms at molecular level. The present results help to understand the balance between the unimolecular (A(AC)1) and bimolecular (A(AC)2) reaction pathways. In contrast to the experimental setting, where one of the two branches is often occluded by the requirement of rather extreme experimental conditions, we have been able to estimate both contributions for all the compounds studied and found that a transition from A(AC)2 to A(AC)1 hydrolysis takes place as acidity increases. A parallel work addresses the neutral and base-catalyzed hydrolysis of lactones.


Subject(s)
Acids/chemistry , Carboxylic Acids/chemical synthesis , Lactones/chemistry , Carboxylic Acids/chemistry , Catalysis , Esters/chemistry , Hydrolysis , Molecular Structure , Quantum Theory , Water/chemistry
5.
J Org Chem ; 78(14): 6868-79, 2013 Jul 19.
Article in English | MEDLINE | ID: mdl-23758295

ABSTRACT

The neutral and base-catalyzed hydrolysis of nine carboxylic acid esters was studied using a hybrid supermolecule-PCM approach including six explicit water molecules. The molecules studied included two linear esters, four ß-lactones, two γ-lactones, and one δ-lactone: ethyl acetate and methyl formate, ß-propiolactone, ß-butyrolactone, ß-isovalerolactone, diketene (4-methyleneoxetan-2-one), γ-butyrolactone, 2(5H)-furanone, and δ-valerolactone. DFT and ab initio methods were used to analyze the features of the various possible hydrolysis mechanisms. For all compounds, reasonable to very good qualitative and quantitative agreement with experimental work was found, and evidence is provided to support long-standing hypotheses regarding the role of solvent molecule as a base catalyst. In addition, novel evidence is presented for the existence of an elimination-addition mechanism in the basic hydrolysis of diketene. A parallel work addresses the acid-catalyzed hydrolysis of lactones.


Subject(s)
Alkalies/chemistry , Lactones/chemistry , Carboxylic Acids/chemistry , Catalysis , Esters/chemistry , Hydrolysis , Molecular Structure , Water/chemistry
6.
Chem Res Toxicol ; 25(12): 2755-62, 2012 Dec 17.
Article in English | MEDLINE | ID: mdl-23171086

ABSTRACT

The chemical reactivity of the mutagenic epoxides (EP) propylene oxide (PO), 1,2-epoxybutane (1,2-EB), and cis- and trans-2,3-epoxybutane (cis- and trans-2,3-EB) with 4-(p-nitrobenzyl)pyridine (NBP), a bionucleophile model for S(N)2 alkylating agents with high affinity for the guanine-N7 position, was investigated kinetically. It was found that three reactions are involved simultaneously: the alkylation reaction of NBP by EP, which yields the corresponding NBP-EP adducts through an S(N)2 mechanism, and EP and NBP-EP hydrolysis reactions. PO and 1,2-EB were seen to exhibit a higher alkylating potential than cis- and trans-2,3-EB. From a study of the correlations between the chemical reactivity (kinetic parameters) and the biological effectiveness of oxiranes, the following conclusions can be drawn: (i) the hydrolysis reactions of epoxides must be taken into account to understand their bioactivity. (ii) The fraction (f) of the alkylating oxirane that forms the adduct and the adduct life (AL) permit the potential of epoxides as bioactive molecules to be rationalized even semiquantitatively; and (iii) alkylation of DNA by epoxides and the O(6)-/N7-guanine adduct ratio are directly related to their mutagenicity in vitro.


Subject(s)
Epoxy Compounds/chemistry , Pyridines/chemistry , Alkylating Agents , DNA Adducts , Epoxy Compounds/metabolism , Kinetics , Pyridines/metabolism
7.
Environ Sci Technol ; 46(24): 13463-70, 2012 Dec 18.
Article in English | MEDLINE | ID: mdl-23163518

ABSTRACT

MX (3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone), a disinfection byproduct present in chlorinated drinking water, is one of the most potent mutagens known. Whereas its genotoxic effects are well documented, the mechanism by which MX exerts such an intense biological effect is still unclear. To gain further insight into both the general reactivity of hydroxyhalofuranones, and especially as regards their genotoxicity, here we report an in silico study of the aqueous reactivity of MX and two less powerful analogues (MXY, in general): (3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone -CMCF- and 3-chloro-4-(methyl)-5-hydroxy-2(5H)-furanone -MCF-). The following aspects were investigated: (i) the acid dissociation and isomerization equilibria of MXY, i.e. the species distribution among the possible isomers; (ii) the one-electron reduction potential of MXY; (iii) the guanosine and adenosine alkylation mechanism by MXY, which leads to covalent-DNA adducts; and (iv) the redox properties of the adducts. No significant differences were observed between MCF, CMCF, and MX, with a single exception: the unimolecular carbon-chlorine cleavage of some MX-nucleotide adducts may afford highly oxidative intermediates, which could be able to remove an electron from contiguous nucleotides directly, especially guanosine. This reaction would provide a pathway for the hypothesized ability of some hydroxyhalofuranones to oxidize DNA.


Subject(s)
Computer Simulation , DNA Damage , Furans/toxicity , Mutagens/toxicity , Adenosine/chemistry , Alkylation/drug effects , DNA Adducts/chemistry , Electrons , Furans/chemistry , Guanosine/chemistry , Kinetics , Mutagens/chemistry , Oxidation-Reduction/drug effects , Solutions , Thermodynamics
8.
Food Chem ; 134(2): 986-91, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-23107717

ABSTRACT

Taurine (2-aminoethanesulphonic acid) is an amino acid-like-compound widely used as an ingredient in some nutraceuticals and energy drinks. Here the interaction of taurine (Tau) with nitrite was investigated. The reactions were carried out mimicking the conditions of the stomach lumen. The conclusions drawn are as follows: (i) Nitrite showed nitrosating capacity on Tau. The rate equation was ν(N)=k(obs)[Tau](o)[nitrite](o)(2), this result suggesting that the yield of nitrosation products in the human stomach would increase sharply with higher nitrate/nitrite intakes; (ii) the experimental results suggest a mechanism for the nitrosation, whose rate-limiting step is bimolecular attack by N(2)O(3); (iii) the nitrosation of taurine affords ethanesultone (ES), which displays alkylating capacity on the nucleophile 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases. Although the NBP alkylation rate for ethanesultone is much higher than those for carcinogenic four-membered ring lactones, resulting in the nitrosation of amino carboxylic acids, the fraction of ES-forming adduct with NBP is much smaller; (iv) in spite of the low risk to human health, since the stomach lumen conditions could be a favourable medium for Tau nitrosation, attention should be paid to potential situations of the concurrence of high contents of taurine and nitrite/nitrate in the diet.


Subject(s)
Alkylating Agents/chemistry , Nitrites/chemistry , Taurine/chemistry , Alkylating Agents/metabolism , Gastric Mucosa/metabolism , Humans , Kinetics , Models, Biological , Nitrites/metabolism , Nitrosation , Stomach/chemistry , Taurine/metabolism
9.
Chem Res Toxicol ; 25(6): 1176-91, 2012 Jun 18.
Article in English | MEDLINE | ID: mdl-22480281

ABSTRACT

Alkylating agents are considered to be archetypal carcinogens. One suitable technique to evaluate the activity of alkylating compounds is the NBP assay. This method is based on the formation of a chromophore in the reaction between the alkylating agent and the nucleophile 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases. NBP is known to react with strong and weak alkylating agents, and much insight into such alkylation mechanisms in vivo can be gained from kinetic study of some alkylation reactions in vitro. Since 1925, the NBP assay has evolved from being a qualitative, analytical tool to becoming a useful physicochemical method that not only allows the rules of chemical reactivity that govern electrophilicity and nucleophilicity to be applied to the reaction of DNA with alkylating agents but also helps to understand some significant relationships between the structure of many alkylation substrates (including DNA) and their chemical and biological responses. Given that advances in this area have the potential to yield both fundamental and practical advances in chemistry, biology, predictive toxicology, and anticancer drug development, this review is designed to provide an overview of the evolution of the NBP method from its early inception until its recent kinetic-mechanistic approach, which allows the pros and cons of NBP as a DNA-model to be analyzed. The validity of NBP as a nucleophilicity model for DNA in general and the position of guanosine at N7 in particular are discussed.


Subject(s)
DNA/chemistry , Pyridines/chemistry , Alkylation , Animals , Humans , Kinetics , Models, Chemical , Pyridines/chemical synthesis
10.
Environ Sci Technol ; 45(20): 9009-16, 2011 Oct 15.
Article in English | MEDLINE | ID: mdl-21910489

ABSTRACT

Hydroxyhalofuranones form a group of genotoxic disinfection byproduct (DBP) of increasing interest. Among them, mucohalic acids (3,4-dihalo-5-hydroxyfuran-2(5H)-one, MXA) are known mutagens that react with nucleotides, affording etheno, oxaloetheno, and halopropenal derivatives. Mucohalic acids have also found use in organic synthesis due to their high functionalization. In this work, the alkylation kinetics of mucochloric and mucobromic acids with model nucleophiles aniline and NBP has been studied experimentally. Also, the alkylation mechanism of nucleosides by MXA has been studied in silico. The results described allow us to reach the following conclusions: (i) based on the kinetic and computational evidence obtained, a reaction mechanism was proposed, in which MXA react directly with amino groups in nucleotides, preferentially attacking the exocyclic amino groups over the endocyclic aromatic nitrogen atoms; (ii) the suggested mechanism is in agreement with both the product distribution observed experimentally and the mutational pattern of MXA; (iii) the limiting step in the alkylation reaction is addition to the carbonyl group, subsequent steps occurring rapidly; and (iv) mucoxyhalic acids, the hydrolysis products of MXA, play no role in the alkylation reaction by MXA.


Subject(s)
DNA/drug effects , Mutagens/chemistry , Alkylation , DNA Damage/drug effects , Disinfection , Molecular Structure , Mutagens/toxicity , Pyridines/chemistry
11.
Org Biomol Chem ; 9(20): 7016-22, 2011 Oct 21.
Article in English | MEDLINE | ID: mdl-21870002

ABSTRACT

The alkylating potential of p-nitrostyrene oxide (pNSO)--a compound used as a substrate to study the activity of epoxide hydrolases as well as in polymer production and in the pharmaceutical industry--was investigated kinetically. The molecule 4-(p-nitrobenzyl)pyridine (NBP), as a model nucleophile for DNA bases, was used as an alkylation substrate. In order to gain insight into the effect of the hydrolysis of pNSO, as well as the hydrolysis of the NBP-pNSO adduct on the pNSO alkylating efficiency, these two competing reactions were studied in parallel with the main NBP-alkylation reaction. The following conclusions were drawn: (i) pNSO reacts through an S(N)2 mechanism, with NBP to form an adduct, pNSO-NBP (AD). The rate equation for the adduct formation is: r = d[AD]/dt = k(alk)[NBP][pNSO]-k(hyd)(AD) [AD] (k(alk), and k(hyd)(AD) being the alkylation rate constant and the NBP-pNSO adduct hydrolysis rate constant, respectively); (ii) the alkylating capacity of pNSO, defined as the fraction of initial alkylating agent that forms the adduct, is similar to that of mutagenic agents as effective as ß-propiolactone. The instability of the pNSO-NBP adduct formed could be invoked to explain the lower mutagenicity shown by pNSO; (iii) the different stabilities of the α and ß-adducts formed between NBP and styrene oxides show that the alkylating capacity f = k(alk)[NBP]/(k(alk)[NBP] + k(hyd)) (k(hyd) being the pNSO hydrolysis rate constant) as well as the alkylating effectiveness, AL = f/k(hyd)(AD), are useful tools for correlating the chemical reactivity and mutagenicity of styrene oxides; (iv) a pNSO-guanosine adduct was detected.


Subject(s)
Alkylating Agents/chemistry , Biomimetic Materials/chemistry , Epoxy Compounds/chemistry , Alkylation , Hydrolysis , Kinetics , Molecular Structure
12.
Org Biomol Chem ; 9(22): 7680-4, 2011 Oct 26.
Article in English | MEDLINE | ID: mdl-21779549

ABSTRACT

Minoxidil (2,4-diamino-6-(piperidin-1'-yl)pyrimidine N(3)-oxide; CASRN 38304-91-5) is a bioactive molecule with several nitrosatable groups widely used as an antihypertensive and antialopecia agent. Here the nitrosation of minoxidil was investigated. The conclusions drawn are as follows: (i) In the pH = 2.3-5.0 range, the minoxidil molecule undergoes aromatic C-nitrosation by nitrite. The dominant reaction was C-5 nitrosation through a mechanism that appears to consist of an electrophilic attack on the nitrosatable substrate by H(2)NO(2)(+)/NO(+), followed by a slow proton transfer; (ii) the reactivity of minoxidil as a C-nitrosatable substrate proved to be 7-fold greater than that of phenol, this being attributed to the preferred para- and ortho-orientations of the two -NH(2) groups at positions 2 and 4 of the minoxidil molecule, which activate electrophilic substitution in the C-5 position through their mesomeric effect. The N-nitrosominoxidil resulting from the nitrosation could be potentially harmful to the minoxidil users.


Subject(s)
Antihypertensive Agents/chemistry , Minoxidil/chemistry , Nitrites/chemistry , Protons , Alopecia/drug therapy , Animals , Antihypertensive Agents/adverse effects , Antihypertensive Agents/pharmacology , Chromatography, Liquid , Dimethylnitrosamine/adverse effects , Dimethylnitrosamine/pharmacology , Drug-Related Side Effects and Adverse Reactions , Humans , Hydrogen-Ion Concentration , Hypertension/drug therapy , Kinetics , Magnetic Resonance Spectroscopy , Minoxidil/adverse effects , Minoxidil/metabolism , Minoxidil/pharmacology , Molecular Structure , Nitrites/metabolism , Nitrosation , Phenol/chemistry , Rats , Stereoisomerism
13.
Org Biomol Chem ; 9(18): 6226-33, 2011 Sep 21.
Article in English | MEDLINE | ID: mdl-21773622

ABSTRACT

Alkylation reactions of the nucleoside guanosine (Guo) by the α,ß-unsaturated compounds (α,ß-UC) acrylonitrile (AN), acrylamide (AM), acrylic acid (AA) and acrolein (AC), which can act as alkylating agents of DNA, were investigated kinetically. The following conclusions were drawn: i) The Guo alkylation mechanism by AC is different from those brought about the other α,ß-UC; ii) for the first three, the following sequence of alkylating potential was found: AN > AM > AA; iii) A correlation between the chemical reactivity (alkylation rate constants) of AN, AM, and AA and their capacity to form adducts with biomarkers was found. iv) Guo alkylation reactions for AN and AM occur through Michael addition mechanisms, reversible in the first case, and irreversible in the second. The equilibrium constant for the formation of the Guo-AN adduct is K(eq) (37 °C) = 5 × 10(-4); v) The low energy barrier (≈10 kJ mol(-1)) to reverse the Guo alkylation by AN reflects the easy reversibility of this reaction and its possible correction by repair mechanisms; vi) No reaction was observed for AN, AM, and AA at pH < 8.0. In contrast, Guo alkylation by AC was observed under cellular pH conditions. The reaction rate constants for the formation of the α-OH-Guo adduct (the most genotoxic isomer), is 1.5-fold faster than that of γ-OH-Guo. vii) a correlation between the chemical reactivity of α,ß-UC (alkylation rate constants) and mutagenicity was found.


Subject(s)
Alkylating Agents/chemistry , Guanosine/chemistry , Acrolein/chemistry , Acrylamide/chemistry , Acrylates/chemistry , Acrylonitrile/chemistry , Alkylation , Carcinogens/chemistry , DNA/chemistry , Kinetics
14.
Water Res ; 45(2): 714-20, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20855100

ABSTRACT

One group of disinfection byproducts of increasing interest are the halogenated furanones, which are formed in the chlorination of drinking water. Among these halofuranones is mucochloric acid (MCA, 3,4-dichloro-5-hydroxyfuran-2(5H)-one), and mucobromic acid (MBA, 3,4-dibromo-5-hydroxyfuran-2(5H)-one). Both mucohalic acids (MXA) are direct genotoxins and potential carcinogens, with the capacity to alkylate the DNA bases guanosine, adenosine and cytosine, and they have been measured in concentrations ranging up to 700 ng/l in tap water. MCA and MBA react in basic aqueous medium to form mucoxyhalic acids (4-halo-3,5-hydroxyfuran-2(5H)-one). Since: i) this reaction may represent the first step in the abiotic decomposition of mucohalic acids, ii) mucoxyhalic acids have been proposed as possible intermediates in the reaction of MXA with DNA, a kinetic study of the reaction mechanism is of interest. Here, the following conclusions were drawn: a) At moderately basic pH, the reaction of mucohalic acids with OH(-) to form mucoxyhalic acids is kinetically significant. b) The nucleophilic attack of hydroxide ions on MXA occurs through a combination of two paths: one of them is first-order in hydroxide whereas the other is second-order and are proposed to occur through the deprotonation of the hydrate of MXA. c) The hydration constants of mucohalic acids -0.23 and 0.17 for MCA and MBA respectively - corresponds to the very significant hydrate concentrations. Since hydrates are not electrophilic, these values imply a decrease in the alkylating capacity of mucohalic acids.


Subject(s)
Furans/chemistry , Water/chemistry , Disinfection , Halogenation , Kinetics , Water Supply
15.
Chem Res Toxicol ; 23(7): 1275-81, 2010 Jul 19.
Article in English | MEDLINE | ID: mdl-20550097

ABSTRACT

Small, highly strained heterocycles are archetypical alkylating agents (oxiranes, beta-lactones, aziridinium, and thiirinium ions). Oxetanes, which are tetragonal ethers, are higher homologues of oxiranes and reduced counterparts of beta-lactones, and would therefore be expected to be active alkylating agents. Oxetanes are widely used in the manufacture of polymers, especially in organic light-emitting diodes (OLEDs), and are present, as a substructure, in compounds such as the widely used antimitotic taxol. Whereas the results of animal tests suggest that trimethylene oxide (TMO), the parent compound, and beta,beta-dimethyloxetane (DMOX) are active carcinogens at the site of injection, no studies have explored the alkylating ability and genotoxicity of oxetanes. This work addresses the issue using a mixed methodology: a kinetic study of the alkylation reaction of 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilicity similar to that of DNA bases, by three oxetanes (TMO, DMOX, and methyloxetanemethanol), and a mutagenicity, genotoxicity, and cell viability study (Salmonella microsome test, BTC E. coli test, alkaline comet assay, and MTT assay). The results suggest either that oxetanes lack genotoxic capacity or that their mode of action is very different from that of epoxides and beta-lactones.


Subject(s)
Alkylating Agents/chemistry , Ethers, Cyclic/chemistry , Alkylating Agents/toxicity , Alkylation , Carcinogens/chemistry , Carcinogens/toxicity , Comet Assay , Ethers, Cyclic/toxicity , Ethylene Oxide/chemistry , Kinetics , Lactones/chemistry
16.
J Org Chem ; 75(5): 1444-9, 2010 Mar 05.
Article in English | MEDLINE | ID: mdl-20121054

ABSTRACT

The formation of chemical species with DNA-damaging and mutagenic activity for bacterial test systems was detected in sorbic acid-nitrite mixtures. 1,4-Dinitro-2-methylpyrrole (NMP), one the main products resulting from the reaction between sorbic acid and nitrite, has mutagenic properties, and here its alkylating capacity was investigated. The conclusions drawn are as follows: (i) In aqueous medium, after the addition of a hydroxide ion and the subsequent loss of nitrite, NMP affords 5-methyl-3-nitro-1H-pyrrol-2-ol. This species is in equilibrium with 5-methyl-3-nitro-1H-pyrrol-2(5H)-one, the effective alkylating agent responsible for the genotoxic capacity of NMP; (ii) 5-methyl-3-nitro-1H-pyrrol-2(5H)-one alkylates 4-(p-nitrobenzyl)pyridine (NBP), a molecule with nucleophilic characteristics similar to those of DNA bases, forming an adduct (AD; epsilon = 1.14 x 10(4) M(-1) cm(-1)); (iii) The calculated energy barrier for the alkylation of NBP for NMP and the value of the fraction of alkylating agent forming the adduct are consistent with the observed mutagenicity of NMP; (iv) The reactivity of NMP can be explained in terms of the instability of the N-NO(2) bond as well as the effect of this group on aromaticity.


Subject(s)
Alkylating Agents/chemistry , DNA/chemistry , Mutagens , Nitrites/chemistry , Pyrroles/chemistry , Sorbic Acid/chemistry , Alkylating Agents/toxicity , Chromatography, High Pressure Liquid , DNA/metabolism , DNA Damage , Magnetic Resonance Spectroscopy , Mass Spectrometry , Microbial Sensitivity Tests , Mutation/drug effects , Pyrroles/toxicity , Salmonella , Spectrophotometry, Ultraviolet , Structure-Activity Relationship
17.
J Phys Chem A ; 113(42): 11423-8, 2009 Oct 22.
Article in English | MEDLINE | ID: mdl-19761202

ABSTRACT

Hydration reactions are relevant for understanding many organic mechanisms. Since the experimental determination of hydration and hemiacetalization equilibrium constants is fairly complex, computational calculations now offer a useful alternative to experimental measurements. In this work, carbonyl hydration and hemiacetalization constants were calculated from the free energy differences between compounds in solution, using absolute and relative approaches. The following conclusions can be drawn: (i) The use of a relative approach in the calculation of hydration and hemiacetalization constants allows compensation of systematic errors in the solvation energies. (ii) On average, the methodology proposed here can predict hydration constants within +/- 0.5 log K(hyd) units for aldehydes. (iii) Hydration constants can be calculated for ketones and carboxylic acid derivatives within less than +/- 1.0 log K(hyd), on average, at the CBS-Q level of theory. (iv) The proposed methodology can predict hemiacetal formation constants accurately at the MP2 6-31++G(d,p) level using a common reference. If group references are used, the results obtained using the much cheaper DFT-B3LYP 6-31++G(d,p) level are almost as accurate. (v) In general, the best results are obtained if a common reference for all compounds is used. The use of group references improves the results at the lower levels of theory, but at higher levels, this becomes unnecessary.

18.
Chem Res Toxicol ; 22(7): 1320-4, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19580248

ABSTRACT

Because chemical species with DNA-damaging and mutagenic activity are formed in sorbate-nitrite mixtures and because sorbic acid sometimes coexists with nitrite occurring naturally or incorporated as a food additive, the study of sorbate-nitrite interactions is important. Here, the alkylating potential of the products resulting from such interactions was investigated. Drawn were the following conclusions: (i) Acetonitrile oxide (ACNO) is the compound responsible for the alkylating capacity of sorbate-nitrite mixtures; (ii) ACNO alkylates 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases, forming an adduct (AD; epsilon = 1.4 x 10(4) M(-1) cm(-1); lambda = 519 nm); (iii) the NBP alkylation reaction complies with the rate equation, r = d[AD]/dt = k(alk)(ACNO)[ACNO][NBP]-k(hyd)(AD)[AD], k(alk)(ACNO) being the NBP alkylation rate constant for ACNO and k(hyd)(AD) the rate constant for the adduct hydrolysis reaction; (iv) the small fraction of ACNO forming the adduct with NBP, as well as the small magnitude of the quotient (k(alk) (ACNO)/k(hyd)(ACNO)) as compared with those reported for other alkylating agents, such as some lactones and N-alkyl-N-nitrosoureas, reveals the ACNO effective alkylating capacity to be less significant; (v) the low value of the NBP-ACNO adduct life (defined as the total amount of adduct present along the progression of the NBP alkylation per unit of alkylating agent concentration) points to the high instability of this adduct; and (vi) the obtained results are in accordance with the low carcinogenicity of ACNO.


Subject(s)
Acetonitriles/chemistry , Alkylating Agents/chemistry , Nitrites/chemistry , Sorbic Acid/chemistry , Acetonitriles/toxicity , Alkylating Agents/toxicity , DNA Damage , Kinetics , Pyridines/chemistry
19.
J Org Chem ; 74(14): 4943-8, 2009 Jul 17.
Article in English | MEDLINE | ID: mdl-19459649

ABSTRACT

A computational study of the aqueous pK(a) of some saturated and unsaturated cyclic and linear esters and ketones was carried out at the DFT-B3LYP 6-31++G(2df,2pd), CBS-Q, and G2 levels, with the integral equation formalism polarizable continuum model for solvation, using a proton exchange mechanism. The influence of unsaturation, position of the double bond, and cyclization were studied. The computational results show that (a) in all cases studied except that of diketene (4-methylene-2-oxetanone), the alpha-beta unsaturated isomer is 20-30 kJ mol(-1) lower in energy that the beta-gamma unsaturated one; (b) alpha-beta unsaturation lowers the pK(a) of an ester approximately 6 units, whereas beta-gamma unsaturation lowers it by approximately 10 units, and cyclization lowers the pK(a) by approximately 3 units. In order to check the predictive power of the methodology, the acid dissociation constant of diketene in water was measured via kinetic study of its base-catalyzed hydrolysis. The pK(a) value obtained (15.2 +/- 0.3) is in keeping with the expected value for a beta-gamma unsaturated beta-lactone. This low value also suggests that deprotonated diketene does not interconvert to a more stable, less acidic alpha-beta unsaturated isomer, which is also consistent with computational results.

20.
J Agric Food Chem ; 56(24): 11824-9, 2008 Dec 24.
Article in English | MEDLINE | ID: mdl-19053359

ABSTRACT

Sorbic acid reacts with nitrite to yield mutagenic products such as 1,4-dinitro-2-methylpyrrole (NMP) and ethylnitrolic acid (ENA). In order to know the stability of these compounds, a kinetic study of their decomposition reactions was performed in the 6.0-9.5 pH range. The conclusions drawn are as follows: (i) The decomposition of NMP occurs through a nucleophilic attack by OH- ions, with the rate equation as follows: r = k(dec)NMP[OH-][NMP] with k(dec)NMP (37.5 degrees C) = 42 +/- 1 M(-1) s(-1). (ii) The rate law for the decomposition of ENA is as follows: r = k(dec)ENA[ENA]K(a)/(K(a) + [H+]), with K(a) being the ENA dissociation constant and k(dec)ENA (37.5 degrees C) = (7.11 +/- 0.04) x 10(-5) s(-1). (iii) The activation energies for NMP and ENA decomposition reactions are, respectively, E(a) = 94 +/- 3 and 94 +/- 1 kJ mol(-1). (iv) The observed values for the decomposition rate constants of NMP and ENA in the pH range of the stomach lining cells, into which these species can diffuse, are so slow that they could be the slow determining step of the alkylation mechanisms by some of the products resulting from NMP and ENA decomposition. Thus, the current kinetic results are consistent with the low mutagenicity of these species.


Subject(s)
Hydroxylamines/chemistry , Mutagens/chemistry , Nitriles/chemistry , Pyrroles/chemistry , Sodium Nitrite/chemistry , Sorbic Acid/chemistry , Kinetics
SELECTION OF CITATIONS
SEARCH DETAIL
...