Kinetic investigation on aqueous decomposition of 2-chloroethylnitrososulfamide

Seridi, Achour; Kadri, Mekki; Abdaoui, Mohamed; Winum, Jean‐Yves; Montéro, Jean-Louis

doi:10.1016/j.bmcl.2005.10.080

Cited by 13 publications

(14 citation statements)

References 30 publications

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“…Chloroethynitrosoureas (CENUs), such as 1,3‐bis‐(2‐chloroethyl)‐1‐nitrosourea (BCNU), 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU) and 1‐(2‐chloroethyl)‐3‐(4‐methylcyclohexyl)‐1‐nitrosourea (meCCNU), have been widely used as chemotherapeutics for the inhibition of leukemia, Hodgkin's disease and various solid tumors . CENUs are unstable in aqueous media and spontaneously decompose to yield chloroethyldiazohydroxides, which give rise to diazonium ions, and perhaps other carbocations . These electrophilic ions damage DNA by alkylation of bases, single/double strand breakages and interstrand crosslinks (ISC) .…”

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confidence: 99%

Quantification of meCCNU‐induced dG‐dC crosslinks in oligonucleotide duplexes by liquid chromatography/electrospray ionization tandem mass spectrometry

Bai

Zhao

Zhong

2011

Rapid Comm Mass Spectrometry

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Chloroethynitrosoureas (CENUs) are important alkylating agents widely used in the treatment of cancers. Decomposition of CENUs generates active electrophilic ions that damage DNA, including the formation of dG-dC crosslinks which represents the most important cytotoxic mechanism of CENUs. In this work, a high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ESI-MS/MS) method was employed to analyze the dG-dC crosslinks induced by 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (meCCNU, Semustine). The direct quantitation of dG-dC crosslinks in oligonucleotide duplexes was achieved by the selected reaction monitoring (SRM) mode using synthesized (15) N(3) -labeled dG-dC as an internal standard. Methods of enzymatic digestion and HPLC separation were developed for obtaining separation and reproducibility of the dG-dC peak in chromatograms. The limit-of-detection (LOD) was determined to be 0.08 nM and the limit-of-quantification (LOQ) was determined to be 0.16 nM. The linearity of the calibration curve was 0.9997 over the range of 0.08 to 32 nM. The precision and accuracy of the method ranged from 1.1 to 6.6% and 96 to 109%, respectively. The recovery of the dG-dC crosslink in the enzymatic hydrolysates from the oligonucleotide duplex was determined to be from 91 to 106%. The results of the validation study indicate that the method is suitable for quantifying dG-dC crosslinks in DNA. Consequently, this method was used to determine meCCNU-induced dG-dC crosslinks in four duplexes with different GC contents. The results showed that the crosslinking fraction (CF) increased as the GC content in the duplex increased, and a relatively low CF was observed in the early period of the reaction.

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confidence: 99%

Quantification of meCCNU‐induced dG‐dC crosslinks in oligonucleotide duplexes by liquid chromatography/electrospray ionization tandem mass spectrometry

Bai

Zhao

Zhong

2011

Rapid Comm Mass Spectrometry

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“…In order to distinguish between chemical and metabolic decomposition, we co-injected the two products found in the decomposition of CENS in aqueous phosphate buffer [4]. The comparison of their chromatographic features with the presumable metabolites produced by decomposition in fetal calf serum showed that:…”

Section: Resultsmentioning

confidence: 99%

“…On the basis of these observations, we have previously developed a new family of alkylating agents structurally related to 2-chloroethylnitrosoureas (CENU) but devoid of any carbamoylating activity: 2-chloroethylnitrososulfamides (CENS) [3]. We could also shown that in aqueous phosphate buffer the decomposition of CENS involved two competitive mechanisms initiated either by the denitrosation of the chloroethylnitrososulfamides (path A) or by a nucleophilic attack on the sulfur atom (path B) to form sulfamate species and chloroethyldiazohydroxide (Scheme 1) which act as adduct of DNA [4].…”

Section: Introductionmentioning

confidence: 97%

Study on the Decomposition of 2‐Chloroethylnitro‐ sosulfamides (CENS) in Serum Using HPLC On‐line Solid Phase Extraction

Seridi

Winum²,

Kadri

et al. 2006

Archiv der Pharmazie

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In this paper we have investigated the kinetic decomposition of 2-chloroethylnitrososulfamides (CENS) in fetal calf serum. The study was monitored by on-line solid phase extraction linked to RP-LC-MS. We demonstrated that CENS are less stable in fetal calf serum than in aqueous buffer at pH 7.4 and 37 degrees C. Moreover, we have shown that partition coefficient of CENS can be correlated to the kinetics decomposition, and we observe that the stability is better for lipophilic CENS. The different metabolites after decomposition have been tentatively identified by RP-HPLC-MS. This study indicates the formation of several metabolites resulting from a mechanism of decomposition more complex than in aqueous phosphate buffer, nevertheless, leading to the same main products.

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“…CENUs undergo decomposition spontaneously under physiological conditions to give rise to alkylating electrophilic centers on the α-carbon and the β-carbon in the chloroethyl group [12][13][14]. The reaction mechanism is shown in Figure 1.…”

Section: Models and Computationsmentioning

confidence: 99%

Quantitative Structure-Activity Relationship Analysis of the Anticancer Activity of Chloroethylnitrosourea Derivatives

Zhao

Zhong

Zhang

2007

2007 1st International Conference on Bioinformatics and Biomedical Engineering

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Chloroethylnitrosoureas (CENUs) are important clinical antitumor agents. In the present work, the quantitative structure-activity relationship (QSAR) of CENUs is investigated by ab initio computations at MP2/6-311G(d,p) level of theory. The activation energies of the electrophilic center formation on the α-and the β-carbon (E a α and E a β ), as well as the octanolwater partition coefficient (LogP), are selected as structural parameters. 37 kinds of CENUs with experimental anticancer therapeutic index (TI) are selected as models. Through numerical fitting for the computational data with the experimental anticancer TI, a computational formula is established to predict the anticancer activity of CENUs. The correct discrimination ratio by computations according to the experimental anticancer TI comes up to 94.6% through a five degrees classification.

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Kinetic investigation on aqueous decomposition of 2-chloroethylnitrososulfamide

Cited by 13 publications

References 30 publications

Quantification of meCCNU‐induced dG‐dC crosslinks in oligonucleotide duplexes by liquid chromatography/electrospray ionization tandem mass spectrometry

Quantification of meCCNU‐induced dG‐dC crosslinks in oligonucleotide duplexes by liquid chromatography/electrospray ionization tandem mass spectrometry

Study on the Decomposition of 2‐Chloroethylnitro‐ sosulfamides (CENS) in Serum Using HPLC On‐line Solid Phase Extraction

Quantitative Structure-Activity Relationship Analysis of the Anticancer Activity of Chloroethylnitrosourea Derivatives

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