Optimized N-phenyl-N′-(2-chloroethyl)ureas as potential antineoplastic agents: Synthesis and growth inhibition activity

Moreau, Emmanuel; Fortin, Sébastien; Desjardins, Michel; Rousseau, Jean L.C.; Petitclerc, Éric; C.‐Gaudreault, René

doi:10.1016/j.bmc.2005.07.048

Cited by 37 publications

(43 citation statements)

References 27 publications

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“…at ASPET Journals on May 9, 2018 jpet.aspetjournals.org newly discovered CEU compound having better growth inhibition (Moreau et al, 2005). In parallel, actin fibers seem to be reduced, confirming the cytoskeletal disorganization following anti-MT treatment.…”

supporting

confidence: 53%

Microtubule-Destabilizing Agents Induce Focal Adhesion Structure Disorganization and Anoikis in Cancer Cells

Deschesnes

Patenaude²,

Rousseau³

et al. 2006

J Pharmacol Exp Ther

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Microtubule disruption provokes cytoskeleton and cell adhesion changes whose importance for apoptosis induction remains unclear. The present study focuses on the functional and the molecular adhesion kinetics that are induced by microtubule disruption-mediated apoptosis. We showed that antimicrotubules induce a biphasic sequence of adhesion response that precedes the onset of apoptosis and focal adhesion kinase hydrolysis. Antimicrotubules first induced an increase of the cellular adhesion paralleled by the raise of focal adhesion sites and actin contractility, which was followed by a sharp decrease of cell adhesion and disorganization of focal adhesion and actin stress fibers. The latter sequence of events ends by cell rounding, detachment from the extracellular matrix, and cell death. Microtubule-disrupting agents induced a sustained paxillin phosphorylation, before the activation of apoptosis, that requires the prior activation of extracellular signal-regulated kinase and p38 but not c-Jun NH 2 -terminal kinase. Interestingly, integrin-linked kinase overexpression rescued the antimicrotubule-mediated loss of cell viability. Altogether, these results propound that antimicrotubule agents induce anoikis through the loss of focal adhesion structure integrity.Focal adhesions (FAs) are specialized complexes of structural and signaling proteins that assemble or disassemble as cell migrate or enter into mitosis. They form, following the integrin-mediated cell attachment to extracellular matrices (ECM), anchoring actin filaments and microtubules (MTs) to the membrane of the cell (Mitra et al., 2005). One of the cornerstone proteins of FA architecture is paxillin (Brown and Turner, 2004). Paxillin connects integrins to the actin cytoskeleton via vinculin and talin (Brown and Turner, 2004) and focal adhesion kinase (FAK), the integrin-linked kinase (ILK) (Nikolopoulos and Turner, 2001). After integrin ligation, FAK undergoes tyrosine autophosphorylation, which triggers interactions with Src-family tyrosine kinases for its maximal activation. The FAK-Src complex further activates several signaling pathways, notably the prosurvival phosphatidylinositol 3-kinase/Akt pathway (Khwaja et al., 1998)

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confidence: 53%

Microtubule-Destabilizing Agents Induce Focal Adhesion Structure Disorganization and Anoikis in Cancer Cells

Deschesnes

Patenaude²,

Rousseau³

et al. 2006

J Pharmacol Exp Ther

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“…The 4-iodo derivative CEU-098 is a bioisostere of the 4-tert-butyl moiety designed to improve the metabolic resistance of CEU-022 (6). Finally, CEU-236, which is a 3-(5-hydroxypentyl) substituted form of CEU, exhibits the highest cell growth inhibition capacity on several tumor cell lines (7,25).…”

Section: Resultsmentioning

confidence: 99%

New Soft Alkylating Agents with Enhanced Cytotoxicity against Cancer Cells Resistant to Chemotherapeutics and Hypoxia

Patenaude

Deschesnes²,

Rousseau³

et al. 2007

Cancer Research

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Chloroethylureas (CEU) are soft alkylating agents that covalently bind to B-tubulin (BTAC) and affect microtubule polymerization dynamics. Herein, we report the identification of a CEU subset and its corresponding oxazolines, which induce cell growth inhibition, apoptosis, and microtubule disruption without alkylating B-tubulin (N-BTAC). Both BTAC and N-BTAC trigger the collapse of mitochondrial potential (#W m ) and modulate reactive oxygen species levels, following activation of intrinsic caspase-8 and caspase-9. Experiments using human fibrosarcoma HT1080 respiratorydeficient cells (R 0 ) and uncoupler of the mitochondrial respiratory chain (MRC) showed that BTAC and N-BTAC impaired the MRC. R 0 cells displayed an increased sensitivity toward N-BTAC as compared with R + cells but, in contrast, were resistant to BTAC or classic chemotherapeutics, such as paclitaxel. , an N-BTAC derivative, triggered massive swelling of isolated mitochondria. This effect was insensitive to cyclosporin A and to Bcl-2 addition. In contrast, adenine nucleotide translocator (ANT) antagonists, bongkrekic acid or atractyloside, diminished swelling induced by . The antiproliferative activities of the N-BTACs CEU-025 and OXA-152 were markedly decreased in the presence of atractyloside. Conversely, pretreatment with cyclosporin A enhanced growth inhibition induced by BTAC and N-BTAC. One of the proteins alkylated by N-BTAC was identified as the voltage-dependent anion channel isoform-1, an ANT partner. Our results suggest that BTAC and N-BTAC, despite their common ability to affect the microtubule network, trigger different cytotoxic mechanisms in cancer cells. The role of mitochondria in these mechanisms and the potential of N-BTAC as a new therapeutic approach for targeting hypoxia-resistant cells are discussed. [Cancer Res 2007;67(5):2306-16]

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“…Anti-␣-tubulin antibody (H-300) and anti-acetylated tubulin antibody (6-11B-1) were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). ICEU, HPCEU, and 4ZComb-CEU were synthesized as described previously by Mounetou et al (2001), Moreau et al (2005), and Fortin et al (2007a), respectively ( Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

“…These unexpected results prompted us to evaluate the effect of more potent CEUs on ␤-tubulin and microtubules. To that end, we have selected 1-(2-chloroethyl)-3-[3-(5-hydroxypentyl)phenyl]urea (HPCEU) (Moreau et al, 2005) and 1-[4-(3-hydroxy-4-methoxystyryl)phenyl]-3-(2-chloroethyl)urea (4ZCombCEU) (Fortin et al, 2007a) that either are more hydrophilic or exhibit a higher affinity to ␤-tubulin, using the original ICEU as positive control. In addition, we have also selected N,NЈ-ethylenebis-(iodoacetamide) (EBI) as control.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the Covalent Binding ofN-Phenyl-N′-(2-chloroethyl)ureas to β-Tubulin: Importance of Glu198 in Microtubule Stability

Fortin¹,

Bouchon²,

Chambon³

et al. 2010

J Pharmacol Exp Ther

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ureas (CEUs) are antimicrotubule agents interacting covalently with ␤-tubulin near the colchicine-binding site (C-BS). Glutamyl 198 residue in ␤-tubulin (Glu198), which is adjacent to the C-BS behind the two potent nucleophilic residues, Cys239 and Cys354, has been shown to covalently react with 1-(2-chloroethyl)-3-(4-iodophenyl)urea (ICEU). By use of mass spectrometry, we have now identified residues in ␤-tubulin that have become modified irreversibly by 1-(2-chloroethyl)-3-[3-(5-hydroxypentyl)phenyl]urea (HPCEU), 1-[4-(3-hydroxy-4-methoxystyryl)phenyl]-3-(2-chloroethyl)urea (4ZCombCEU), and N,NЈ-ethylenebis(iodoacetamide) (EBI). The binding of HP-CEU and 4ZCombCEU to ␤-tubulin resulted in the acylation of Glu198, a protein modification of uncommon occurrence in living cells. Prototypical CEUs then were used as molecular probes to assess, in mouse B16F0 and human MDA-MB-231 cells, the role of Glu198 in microtubule stability. For that purpose, we studied the effect of Glu198 modification by ICEU, HPCEU, and 4ZCombCEU on the acetylation of Lys40 on ␣-tubulin, a key indicator of microtubule stability. We show that modification of Glu198 by prototypical CEUs correlates with a decrease in Lys40 acetylation, as observed also with other microtubule depolymerizing agents. Therefore, CEU affects the stability and the dynamics of microtubule, likewise a E198G mutation, which is unusual for xenobiotics. We demonstrate for the first time that EBI forms an intramolecular cross-link between Cys239 and Cys354 of ␤-tubulin in living cells. This work establishes a novel basis for the development of future chemotherapeutic agents and provides a framework for the design of molecules useful for studying the role of Asp and Glu residues in the structure/ function and the biological activity of several cellular proteins under physiological conditions.

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Optimized N-phenyl-N′-(2-chloroethyl)ureas as potential antineoplastic agents: Synthesis and growth inhibition activity

Cited by 37 publications

References 27 publications

Microtubule-Destabilizing Agents Induce Focal Adhesion Structure Disorganization and Anoikis in Cancer Cells

Microtubule-Destabilizing Agents Induce Focal Adhesion Structure Disorganization and Anoikis in Cancer Cells

New Soft Alkylating Agents with Enhanced Cytotoxicity against Cancer Cells Resistant to Chemotherapeutics and Hypoxia

Characterization of the Covalent Binding ofN-Phenyl-N′-(2-chloroethyl)ureas to β-Tubulin: Importance of Glu198 in Microtubule Stability

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