Alkylating potential of <i>N</i>‐phenyl‐<i>N</i>‐nitrosourea

Manso, José A.; Pérez‐Prior, María Teresa; Gómez‐Bombarelli, Rafael; González‐Pérez, Marina; Céspedes, Isaac F.; García‐Santos, M. P.; Calle, Emilio; Casado, Julio

doi:10.1002/poc.1456

Cited by 5 publications

(5 citation statements)

References 21 publications

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“…N- Alkyl- N- nitrosoureas decompose in water to form diazonium ions, the effective alkylating agents. The benzenediazonium ion reacts with NBP about 20,000-fold more slowly than methyldiazonium, which is consistent with the fact that the methyldiazonium ion shows higher carcinogenicity in animal tests …”

Section: Uses Of the Nbp Methods And Alkylation Mechanismssupporting

confidence: 79%

“…The benzenediazonium ion reacts with NBP about 20,000-fold more slowly than methyldiazonium, which is consistent with the fact that the methyldiazonium ion shows higher carcinogenicity in animal tests. 197 Mechanistic conclusions have also been obtained from this approach to the kinetic NBP assay. The relative hydrolysis and alkylation rates of N-diazoacetyl derivatives of amino acids suggest that degradation is a prerequisite for alkylation.…”

Section: Scheme 3 Generic Alkylation Mechanismmentioning

confidence: 91%

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Potential of the NBP Method for the Study of Alkylation Mechanisms: NBP as a DNA-Model

Gómez‐Bombarelli

González‐Pérez

Calle

et al. 2012

Chem. Res. Toxicol.

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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.

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Section: Uses Of the Nbp Methods And Alkylation Mechanismssupporting

confidence: 79%

Section: Scheme 3 Generic Alkylation Mechanismmentioning

confidence: 91%

Potential of the NBP Method for the Study of Alkylation Mechanisms: NBP as a DNA-Model

Gómez‐Bombarelli

González‐Pérez

Calle

et al. 2012

Chem. Res. Toxicol.

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“…In previous work we studied the in vitro reactivity of several alkylating compounds capable of forming DNA adducts: sorbic acid [4] and sorbates [5], nitrosoureas [6,7], p-nitrostyrene oxide [8], and lactones [9][10][11][12]. The results revealed a correlation between the carcinogenicity of the substances and their reactivity with 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilicity similar to that of DNA [13,14].…”

Section: Introductionmentioning

confidence: 97%

The reactivity of vinyl compounds as alkylating agents

et al. 2012

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The reactions of 4-(p-nitrobenzyl)pyridine (a trap for alkylating agents with nucleophilicity similar to that of DNA) with the vinyl compounds acrylonitrile, acrylamide, acrylic acid, and acrolein, which can act as alkylating agents of DNA, were investigated. The following conclusions were drawn: (1) vinyl compounds show an alkylating capacity on 4-(p-nitrobenzyl)pyridine. The sequence of the alkylating potential was found to be acrylonitrile [ acrylamide [ acrylic acid [ acrolein (alkylation with acrolein was not observed after 3 weeks). The formation of adducts with acrylonitrile was approximately 10-and 100-fold faster than with acrylamide and acrylic acid, respectively, which is consistent with its highly carcinogenic and mutagenic activity. (2) 4-(p-Nitrobenzyl)pyridine alkylation reactions by vinyl compounds occur through an enthalpycontrolled Michael addition mechanism. The values for the free energy of activation for these reactions with 4-(p-nitrobenzyl)pyridine were: D à G°(37°C) acrylonitrile, 98 ± 1 kJ mol -1 ; acrylamide, 105 ± 2 kJ mol -1 ; acrylic acid, 109 ± 1 kJ mol -1 . (3) Application of Hammett treatment to the kinetic results revealed that these alkylation reactions occur through nucleophilic attack, being moderately accelerated by electron-withdrawing groups.

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“…The second approach involved the study of their reactivity with 4-( p -nitrobenzyl)pyridine (NBP), a trap for alkylating agents of nucleophilicity similar to that of DNA bases , . NBP is known to react with strong , and weak − alkylating agents, and much insight into the alkylation mechanisms in vivo can be gained from the kinetic study of this reaction in vitro − .…”

Section: Introductionmentioning

confidence: 99%

Alkylating Potential of Oxetanes

Gómez‐Bombarelli

Palma

Martins

et al. 2010

Chem. Res. Toxicol.

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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.

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Alkylating potential of N‐phenyl‐N‐nitrosourea

Cited by 5 publications

References 21 publications

Potential of the NBP Method for the Study of Alkylation Mechanisms: NBP as a DNA-Model

Potential of the NBP Method for the Study of Alkylation Mechanisms: NBP as a DNA-Model

The reactivity of vinyl compounds as alkylating agents

Alkylating Potential of Oxetanes

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