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

Gómez‐Bombarelli, Rafael; González‐Pérez, Marina; Calle, Emilio; Casado, Julio

doi:10.1021/tx300065v

Cited by 20 publications

(43 citation statements)

References 196 publications

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“…6 This, together with the preference of SO for the N7-position of guanine over other nucleophile positions of the DNA bases, 7,8,13,18,27 suggests that NBP is a suitable model to investigate the reactivity of SO with DNA. 21 The good fitting of the experimental A AD /t data obtained under neutral conditions ( Figure 2) to eq 7 supports the proposed mechanism.…”

Section: ■ Introductionsupporting

confidence: 67%

Alkylating Potential of Styrene Oxide: Reactions and Factors Involved in the Alkylation Process

González‐Pérez

Gómez‐Bombarelli

Pérez‐Prior

et al. 2014

Chem. Res. Toxicol.

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The chemical reactivity of styrene-7,8-oxide (SO), an alkylating agent with high affinity for the guanine–N7 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. UV–vis 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 β-NBP–SO adduct through an SN2 mechanism; (b) the acid-catalyzed formation of the stable α-NBP–SO adduct through an SN2′ mechanism; (c) the base-catalyzed hydrolysis of the β-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: kalkβ = (2.1 ± 0.3) × 10–4 M–1 s–1, kalkα = (1.0 ± 0.1) × 10–4 M–1 s–1, khydAD = (3.06 ± 0.09) × 10–6 s–1, and khyd = (4.2 ± 0.9) × 10–6 s–1. 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 5.81–7.69 range, the fraction of total adducts formed increased from 24% to 90% of the initial SO, whereas the adduct lifetime of the unstable β-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.

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Section: ■ Introductionsupporting

confidence: 67%

Alkylating Potential of Styrene Oxide: Reactions and Factors Involved in the Alkylation Process

González‐Pérez

Gómez‐Bombarelli

Pérez‐Prior

et al. 2014

Chem. Res. Toxicol.

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“…25 These results are coherent with the known final products of MXY−nucleotide reactions and suggest that MXY are moderately strong alkylating agents. Nevertheless, they are weaker (even in their more active E form) than similar compounds, for example mucohalic acids, 26 or other genotoxic compounds, 34 which, however, exhibit lower activity in genotoxicity assays. Also, CMCF has a much lower alkylation barrier, which suggests an increased alkylating ability, contrary to the trends observed in biological assays.…”

Section: ■ Methodology and Computational Detailsmentioning

confidence: 99%

DNA Damage by Genotoxic Hydroxyhalofuranones: An in Silico Approach to MX

Gómez‐Bombarelli

Calle

Casado

2012

Environ. Sci. Technol.

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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.

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“…A popular and simple technique to evaluate the alkylating activity of N-mustard compounds is the NBP assay [23]. In this assay, the nucleophile 4-(p-nitrobenzyl)pyridine (NBP) reacts with the tested alkylating agent and generates a chromophore that can be spectroscopically followed (Fig.…”

Section: Relative Reactivity Of the N-mustards 10a And 10bmentioning

confidence: 99%

“…The comparative alkylation rates of chlorambucil, 10a, and 10b were determined by the NBP colorimetric assay, following the emergence of the blue intermediates by HPLC (at k = 455 nm) from the reaction of each compound with NBP [23]. The K alk (in this case K alk = K 0 disregarding K hyd and K dec ) values were calculated [27] using:…”

Section: Relative Reactivity Of the N-mustards 10a And 10bmentioning

confidence: 99%

Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities

et al. 2015

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Research on DNA binding antitumor agents has been classically steered by either non-covalent (DNA intercalation) or covalent (DNA alkylation) interactions. In this context bi-functional anticancer molecules are particularly attractive since they are capable of sequential DNA intercalation followed by DNA alkylation. Here we describe the synthesis and in vitro anticancer activity of bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives. Cell viability assays indicate that our amonafide-N-mustard chimeras are selective, effective only on certain tumor cell lines, and less toxic toward nonmalignant cells than the drug amonafide. The biological activities of the bi-functional derivatives presented here are encouraging and the compounds are suitable for further optimization and in vivo studies. Graphical Abstract Here we describe the synthesis and in vitro anticancer activity of three bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives presenting both DNA intercalation and alkylation capabilities. Cell viability assays indicate that these amonafide-N-mustard chimeras are effective only on certain tumor cell lines and are less toxic towards non-malignant cells than their parent drug: amonafide.Electronic supplementary material The online version of this article (

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

Cited by 20 publications

References 196 publications

Alkylating Potential of Styrene Oxide: Reactions and Factors Involved in the Alkylation Process

Alkylating Potential of Styrene Oxide: Reactions and Factors Involved in the Alkylation Process

DNA Damage by Genotoxic Hydroxyhalofuranones: An in Silico Approach to MX

Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities

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