A new family of potential oncostatics: 2-chloroethylnitrososulfamides (CENS)—I. Synthesis, structure, and pharmacological evaluation (preliminary results)

Abdaoui, Mohamed; Dewynter, Georges; Aouf, Nourredine; Favre, Gilles; Morére, Alain; Montéro, Jean-Louis

doi:10.1016/0968-0896(96)00118-6

Cited by 40 publications

(23 citation statements)

References 21 publications

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“…In this context, a new family of alkylating agents named 2-chloroethylnitrososulfamides, structurally related to 2-chloroethylnitrosoureas but devoid of any carbamoylating activity were designed (Abdaoui et al, 1996). We recently reported the synthesis of nitrososulfamide analogs of fotemustine ( Fig.…”

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confidence: 99%

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Passagne¹,

Evrard²,

Winum³

et al. 2003

J Pharmacol Exp Ther

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Fotemustine is a third generation chloroethylnitrosourea that has demonstrated significant antitumoral effects in malignant melanoma. However, its use is somewhat limited by its toxic side effects and chemoresistance caused by direct repair of O 6 -alkyl groups by the enzyme O 6 -methylguanine DNA-methyltransferase (MGMT). The aim of this work was to determine to what extent the expression of MGMT influences cytotoxicity, DNA damage, and apoptosis induced by new nitrososulfamide analogs of fotemustine (compounds 4 and 8), which have previously demonstrated interesting antiproliferative properties. We carried out complementary strategies that consisted of MGMT cDNA transfection in CAL77 MerϪ melanoma cells and of MGMT inhibition with O 6 -benzylguanine (BG) in A375 Merϩ melanoma cells. MGMT-transfected cells were 7 to 9 times less sensitive to fotemustine than parent cells, whereas no difference between the transfected and parent cells was observed for nitrososulfamide analogs. The cytotoxicity of these analogs vis à vis a MGMT-proficient A375 melanoma cell line was approximately 3 times greater than that of fotemustine. Coincubation of these cells with O 6 -benzylguanine significantly increased the cytotoxicity of fotemustine and compound 8, whereas BG had little effect on the cytotoxicity of compound 4. Furthermore, DNA fragmentation determined by a comet assay was greater with nitrososulfamide analogs than with fotemustine. O 6 -benzylguanine increased DNA fragmentation for fotemustine and compound 8, but not for compound 4, which induced comets with a typical apoptotic appearance. The ability of this compound to induce apoptosis in the absence of BG was confirmed by a specific enzyme-linked immunosorbent assay apoptotic assay using a single-stranded DNA monoclonal antibody.

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confidence: 99%

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Passagne¹,

Evrard²,

Winum³

et al. 2003

J Pharmacol Exp Ther

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“…The 2-chloroethylnitrososulfamide molecules used in our theoretical study have been prepared in our laboratory by Abdaoui et al [2,3]. They are shown in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that this problem can be avoided by synthesizing a new family of compounds in which the nitrosourea function is replaced by the sulfonyl group [2]. It has also been shown that these 2-chloroethylnitrososulfamide compounds (CENS) were very active antitumor agents and could be considered new typical mutagenic and carcinogenic compounds [3]. Molecular modeling has become a useful tool for examining different interactions in molecules [4].…”

Section: Introductionmentioning

confidence: 99%

Theoretical Study of Some Nitrososulfamide Compounds with Antitumor Activity

2004

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Abstract:The lowest-energy conformations of four 2-chloroethylnitrososulfamides were determined using the MM+ molecular mechanics method as implemented in Hyperchem 6.0. Some of the calculated structural parameters, angles and bonds lengths were compared with the crystal structure data of N-nitroso-N-(2-chloroethyl)-N'-sulfamoylproline. Using MM+, AM1 and PM3 the anti conformation was predicted to be more stable than the syn conformation in each of these compounds. With these methods we found that the relative energy of the transition state (TS) was considerably higher, but with the ab initio method using RHF with minimal basic function STO-3G we found that the syn conformation is predicted to be slightly more stable. The determination of some atomic charges of a selection of atoms on the syn, anti and TS structures of the various compounds provided some details about the nature of the transition state.

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“…The CENS sample were prepared and purified as previously described [3,14]. The water used was distilled and purified through a Milli-Q system to give a resistivity of 18 X/cm (Millipore).…”

Section: Experimental Chemicalsmentioning

confidence: 99%

“…The mechanism of action of these drugs has been extensively studied and the therapeutic efficacies of CENUs are known to be related to their spontaneous decompositions to generate both electrophilic species which alkylate DNA and isocyanates which carbamoylate proteins especially DNA repair proteins, contributing substantially to toxic side effects [2]. 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: 99%

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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A new family of potential oncostatics: 2-chloroethylnitrososulfamides (CENS)—I. Synthesis, structure, and pharmacological evaluation (preliminary results)

Cited by 40 publications

References 21 publications

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Theoretical Study of Some Nitrososulfamide Compounds with Antitumor Activity

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

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A new family of potential oncostatics: 2-chloroethylnitrososulfamides (CENS)—I. Synthesis, structure, and pharmacological evaluation (preliminary results)

Cited by 40 publications

References 21 publications

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O6-Methylguanine DNA-Methyltransferase Expression

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O6-Methylguanine DNA-Methyltransferase Expression

Theoretical Study of Some Nitrososulfamide Compounds with Antitumor Activity

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

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Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression