Synthesis of 4-tert-butyl-3-(2-chloro -[-2-14C]ethyl)ureido benzene

Azim, Elmostafa; Dupuy, J. M.; Maurizis, Jean‐Claude; C.‐Gaudreault, René; Veyre, A.; Madelmont, Jean‐Claude

doi:10.1002/(sici)1099-1344(199707)39:7<559::aid-jlcr4>3.0.co;2-3

Cited by 3 publications

(4 citation statements)

References 6 publications

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“…(25) The biodistribution of CEU analogues to organs of the gastrointestinal tract suggests that they might be promising new drugs for the treatment of colorectal cancers. 32,33 Several CEU subsets were also found to be devoid of antimicrotubule affinity and to bind covalently to proteins such as thioredoxin isoform 1, 34−36 prohibitin 1,(37) and the mitochondrial voltage-dependent anion channel 1. (38)…”

Section: Introductionmentioning

confidence: 99%

“…The acylation of Glu198 leads to microtubule depolymerization, hypoacetylation of Lys40 on α-tubulin, cytoskeleton disruption, and anoikis. , CEU analogues such as 1-(2-chloroethyl)-3-(4-iodophenyl)urea ( 5 ) − or 1-(2-chloroethyl)-3-(3-(5-hydroxypentyl)phenyl)urea ( 6 ) − inhibit angiogenesis and tumor growth in three distinct animal models . The biodistribution of CEU analogues to organs of the gastrointestinal tract suggests that they might be promising new drugs for the treatment of colorectal cancers. , Several CEU subsets were also found to be devoid of antimicrotubule affinity and to bind covalently to proteins such as thioredoxin isoform 1, − prohibitin 1, and the mitochondrial voltage-dependent anion channel 1 …”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4

et al. 2011

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Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2H)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G2/M phase and bind to the colchicine-binding site on β-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds 36, 44, and 45 efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structure–activity relationships.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4

et al. 2011

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“…The choice of the CT-26 colon carcinoma model was based on a previous biopharmaceutical evaluation using i.p. administration of [ 14 C]-tBCEU in mice, showing that tBCEU accumulates strongly into organs of the gastrointestinal tract such as liver, stomach, duodenum, colon, and kidney (7,9). The affinity of the drug for these tissues suggested a potential usefulness of tBCEU against these resilient cancers.…”

Section: Discussionmentioning

confidence: 91%

“…It is noteworthy that several CEUs were shown to disrupt microtubule assembly leading to a profound effect on cell cycle and on cell death (5). Mechanistic studies using carbon-14-labeled tBCEU (6,7) clearly established the irreversible binding of CEUs to cytosolic proteins through an alkylation mechanism (5). In these experiments, we identified that ␤-tubulin was one of the proteins putatively involved in the antimicrotubule effect observed when using tBCEU (5).…”

Section: Introductionmentioning

confidence: 99%

Antiangiogenic and Antitumoral Activity of Phenyl-3-(2-Chloroethyl)Ureas

Petitclerc

Deschesnes²,

Côté³

et al. 2004

Cancer Research

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The development of new anticancer agents with lower toxicity, higher therapeutic index, and weaker tendency to induce resistant phenotypes in tumor cells is a continuous challenge for the scientific community. Toward that end, we showed previously that a new class of soft alkylating agents designed as phenyl-3-(2-chloroethyl)ureas (CEUs) inhibits tumor cell growth in vitro and that their efficiency is not altered by clinically relevant mechanisms of resistance such as overexpression of multidrug resistance proteins, increase in intracellular concentration of glutathione and/or glutathione S-transferase activity, alteration of topoisomerase II, and increased DNA repair. Mechanistic studies have showed recently that the cytotoxic activity of several CEUs was mainly related to the disruption of microtubules. Here, we present results supporting our assumption that 4-tert-butyl-[3-(2-chloroethyl)ureido]phenyl (tBCEU) (and its bioisosteric derivative 4-iodo-[3-(2-chloroethyl)ureido]phenyl (ICEU) are potent antimicrotubule agents both in vitro and in vivo. They covalently bind to beta-tubulin, leading to a microtubule depolymerization phenotype, consequently disrupting the actin cytoskeleton and altering the nuclear morphology. Accordingly, tBCEU and ICEU also inhibited the migration and proliferation of endothelial and tumor cells in vitro in a dose-dependent manner. It is noteworthy that ICEU efficiently blocked angiogenesis and tumor growth in three distinct animal models: (a) the Matrigel plug angiogenesis assay; (b) the CT-26 tumor growth assay in mice; and (c) the chick chorioallantoic membrane tumor assay. In addition, we present evidence that CEU cytotoxicity is unaffected by additional resistance mechanisms impeding tumor response to DNA alkylating agents such as cisplatin, namely the cell adhesion mediated-drug resistance mechanism, which failed to influence the cytocidal activity of CEUs. On the basis of the apparent innocuousness of CEUs, on their ability to circumvent many classical and recently described tumor cell resistance mechanisms, and on their specific biodistribution to organs of the gastrointestinal tract, our results suggest that CEUs represent a promising new class of anticancer agents.

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Chloroethyl urea derivatives block tumour growth and thioredoxin-1 nuclear translocation

Patenaude

Fortin

Deschenes

et al. 2010

Can. J. Physiol. Pharmacol.

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Aryl chloroethyl ureas (CEUs) are new protein alkylating agents exhibiting anticancer activity both in vitro and in vivo. We report herein that 14C-labeled CEU derivatives, designated CEU-025 and CEU-027, covalently bind to thioredoxin-1 (TRX1). Covalent binding of these molecules slightly decreases the disulfide-reducing activity of recombinant TRX1, when compared with the effect of strong thioalkylating agents such as N-ethylmaleimide. Moreover, site-directed mutagenesis and diamide competition assays demonstrated that TRX1 cysteinyl residues are not the prime targets of CEUs. CEU-025 abrogates the nuclear translocation of TRX1 in human cancer cells. In addition, we show that CEU-025 can block TRX1 nuclear translocation induced by cisplatin. Unexpectedly, pretreatment with sublethal CEU-025 concentrations that block TRX1 nuclear translocation protected the cells against cisplatin cytotoxicity. Overexpression of TRX1 in HT1080 fibrosarcoma cells attenuated CEU-025 cytotoxicity, while its suppression using TRX1-specific siRNA increased the effects of CEU-025, suggesting that loss of function of TRX1 is involved, at least in part, in the cytotoxic activity of CEU-025. These results suggest that CEU-025 and CEU-027 exhibit anticancer activity through a novel, unique mechanism of action. The importance of TRX1 and the dependence of the cytotoxicity of CEU-025 and CEU-027 on TRX1 intracellular localization are also discussed.

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Synthesis of 4-tert-butyl-3-(2-chloro -[-2-14C]ethyl)ureido benzene

Cited by 3 publications

References 6 publications

Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4

Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4

Antiangiogenic and Antitumoral Activity of Phenyl-3-(2-Chloroethyl)Ureas

Chloroethyl urea derivatives block tumour growth and thioredoxin-1 nuclear translocation

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