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Fortin, Sébastien

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Fortin

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Sébastien

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Université Laval. Faculté de pharmacie

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Voici les éléments 1 - 10 sur 11
  • PublicationAccès libre
    Optimized N-phenyl-N'-(2-chloroethyl)ureas as potential antineoplastic agents: synthesis and growth inhibition activity
    (Oxford Pergamon, 2005-09-13) Fortin, Sébastien; Rousseau, Jean; Petitclerc, Éric; Desjardins, Michel; C. Gaudreault, René.; Moreau, Emmanuel
    In our ongoing research program aimed at the optimization of microtubule-self-assembly disrupting agents, we have prepared three series of phenylurea analogues (CEU), derived from N-(3-ω-hydroxyalkyl or 4-ω-hydroxyalkyl or 3-ω-hydroxyalkynyl)-phenyl-N′-(2-chloroethyl)ureas. Most compounds exhibit potent growth inhibitory activity on human colon carcinoma HT-29, human skin melanoma M21, and human breast carcinoma MCF-7 tumor cell lines, with a GI50 ranging from 250 nM to 8 μM. Among these new molecules, three CEUs exhibit GI50 in the nanomolar range. They are more potent by approximately an order of magnitude than previously described CEU analogues. As such, they are attractive hit compounds for the development of potent new alkylating antitubulin drugs.
  • PublicationAccès libre
    A comparative molecular field and comparative molecular similarity indices analyses (CoMFA and CoMSIA) of N-phenyl-N'-(2-chloroethyl)urea targeting the colchicine-binding site as anticancer agents
    (Pergamon, 2007-11-05) Fortin, Sébastien; Labrie, Philippe; C. Gaudreault, René.; Wei, Lianhu; Moreau, Emmanuel; Kotra, Lakshmi P.
    To decipher the mechanism underlying the covalent binding of N-phenyl-N′-(2-chloroethyl)ureas (CEU) to the colchicine-binding site on βII-tubulin and to design new and selective antimitotic drugs, we developed 3D quantitative structure–activity relationships (3D-QSAR) models using CoMFA and CoMSIA analyses. The present study correlates the cell growth inhibition activities of 56 structurally related CEU derivatives to several physicochemical parameters representing steric, electrostatic, and hydrophobic fields. Both CoMFA and CoMSIA models using two different optimum numbers of components (ONC) 10 and 4, respectively, gave good internal predictions and their cross-validated r2 values were between 0.639 and 0.743. These comprehensive CoMFA and CoMSIA models are useful in understanding the structure–activity relationships of CEU. The two models were compared to the X-ray crystal structure of the complex of tubulin–colchicine and analyzed for similarities between the two modes of analysis. These models will inspire the design of new CEU derivatives with enhanced inhibition of tumor cell growth and targeting specificity of βII-tubulin and the cytoskeleton.
  • PublicationAccès libre
    Quick and simple detection technique to assess the binding of antimicrotubule agents to the colchicine-binding site
    (Springer Nature, 2010-04-08) Fortin, Sébastien; Côté, Marie-France; Petitclerc, Éric; Lacroix, Jacques M.; C. Gaudreault, René.; Moreau, Emmanuel
    Development of antimitotic binding to the colchicine-binding site for the treatment of cancer is rapidly expanding. Numerous antimicrotubule agents are prepared every year, and the determination of their binding affinity to tubulin requires the use of purified tubulins and radiolabeled ligands. Such a procedure is costly and time-consuming and therefore is limited to the most promising candidates. Here, we report a quick and inexpensive method that requires only usual laboratory resources to assess the binding of antimicrotubules to colchicine-binding site. The method is based on the ability of N,N'-ethylene-bis(iodoacetamide) (EBI) to crosslink in living cells the cysteine residues at position 239 and 354 of β-tubulin, residues which are involved in the colchicine-binding site. The β-tubulin adduct formed by EBI is easily detectable by Western blot as a second immunoreacting band of β-tubulin that migrates faster than β-tubulin. The occupancy of colchicine-binding site by pertinent antimitotics inhibits the formation of the EBI: β-tubulin adduct, resulting in an assay that allows the screening of new molecules targeting this binding site.
  • PublicationAccès libre
    N-Phenyl-N’-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents. part 3 : role of carbonyl group
    (Oxford Pergamon, 2007-10-27) Fortin, Sébastien; Rousseau, Jean; Lacroix, Jacques M.; C. Gaudreault, René.; Patenaude, Alexandre.; Moreau, Emmanuel
    n the course of the development of N-phenyl-N′-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents, we investigated the effect of carbonylated substituting chains of the aromatic ring of CEU on their covalent binding to the colchicine-binding site (C-BS). In this study, we found that CEU, 5e, 5f, 8e, and 8f substituted by either a methyl ester or a methyl ketyl group at the ω-position exhibited a significant antiproliferative activity on HT-29, M21, and MCF-7 tumor cells. SDS–PAGE assays and cell cycle analysis confirmed that 5e, 5f, 8e, and 8f covalently bind to the C-BS and arrest the cell division in G2/M phase. Surprisingly, the presence of ω-carboxyl, ω-ethyl esters or ω-amides decreased significantly both the antiproliferative activity and the specificity toward β-tubulin.
  • PublicationRestreint
    Characterization of the covalent binding of N-phenyl-N'-(2-chloroethyl)ureas to β-tubulin : importance of glutamic acid 198 in microtubule stability
    (American Society for Pharmacology and Experimental Therapeutics, 2011-01-18) Fortin, Sébastien; Bouchon, Bernadette; Lacroix, Jacques M.; Chambon, Christophe; C. Gaudreault, René.; Moreau, Emmanuel; Chezal, Jean-Michel; Degoul, Françoise
    N-Phenyl-N′-(2-chloroethyl)ureas (CEUs) are antimicrotubule agents interacting covalently with β-tubulin near the colchicine-binding site (C-BS). Glutamyl 198 residue in β-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 β-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,N′-ethylenebis(iodoacetamide) (EBI). The binding of HPCEU and 4ZCombCEU to β-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 α-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 β-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.
  • PublicationAccès libre
    Intramolecular cyclization of N-phenyl N’(2-chloroethyl)ureas leads to active N-phenyl-4,5-dihydrooxazol-2-amines alkylating b-tubulin Glu198 and prohibitin Asp40
    (2001-03-01) Trzeciakiewicz, Anna; Fortin, Sébastien; Lacroix, Jacques M.; C. Gaudreault, René.; Moreau, Emmanuel; Chambon, Christophe; Communal, Yves; Chezal, Jean-Michel; Miot-Noirault, Elisabeth; Bouchon, Bernadette; Degoul, Françoise
    The cyclization of anticancer drugs into active intermediates has been reported mainly for DNA alkylating molecules including nitrosoureas. We previously defined the original cytotoxic mechanism of anticancerous N-phenyl-N'-(2-chloroethyl)ureas (CEUs) that involves their reactivity towards cellular proteins and not against DNA; two CEU subsets have been shown to alkylate β-tubulin and prohibitin leading to inhibition of cell proliferation by G₂/M or G₁/S cell cycle arrest. In this study, we demonstrated that cyclic derivatives of CEUs, N-phenyl-4,5-dihydrooxazol-2-amines (Oxas) are two- to threefold more active than CEUs and share the same cytotoxic properties in B16F0 melanoma cells. Moreover, the CEU original covalent binding by an ester linkage on β-tubulin Glu198 and prohibitin Asp40 was maintained with Oxas. Surprisingly, we observed that Oxas were spontaneously formed from CEUs in the cell culture medium and were also detected within the cells. Our results suggest that the intramolecular cyclization of CEUs leads to active Oxas that should then be considered as the key intermediates for protein alkylation. These results will be useful for the design of new prodrugs for cancer chemotherapy.
  • PublicationAccès libre
    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
    (ACS Publications, 2011-05-23) Fortin, Sébastien; Wei, Lianhu; Côté, Marie-France; Petitclerc, Éric; Lacroix, Jacques M.; C. Gaudreault, René.; Moreau, Emmanuel; Kotra, Lakshmi P.
    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.
  • PublicationAccès libre
    Mechanism of action of N-phenyl-N'-(2-chloroethyl)ureas in the colchicine-binding site at the interface between a- and b-tubulin
    (Pergamon, 2009-04-01) Fortin, Sébastien; Wei, Lianhu; Labrie, Philippe; Petitclerc, Éric; C. Gaudreault, René.; Moreau, Emmanuel; Kotra, Lakshmi P.
    Computational tools such as CoMSIA and CoMFA models reported in a recent study revealed the structure–activity relationships ruling the interactions occurring between hydrophobic N-phenyl-N′-(2-chloroethyl)ureas (CEU) and the colchicine-binding site (C-BS) on βΙΙ-tubulin. Here, we describe the mechanisms involved in the covalent binding of three subsets of CEU derivatives to the C-BS. The FlexiDock experiments confirmed that the interaction of non-covalent portions of the CEU auxophore moiety of CEU is involved in the binding of the drug to the C-BS facilitate the nucleophilic attack of Glu-β198 rather than Cys-β239. In addition, these studies suggest that Cys-β239 together with Asn-α99, Ser-α176, Thr-α177, Leu-β246, Asn-β247, Ala-β248, Lys-β252 and Asn-β256 are implicated in the stabilization of a C-BS–CEU complex prior to the acylation of Glu-β198 by CEU. Our molecular models propose the formation of a stabilized C-BS–CEU complex before the completion of the Glu-β198 acylation; acylation triggering conformational changes of β-tubulin, microtubule depolymerization and anoikis. The computational models presented here might be useful to the design of selective and more potent C-BS inhibitors. Of interest, in vivo acylation of acidic amino acid residues by xenobiotics is an unusual reaction and may open new approaches for the design of irreversible protein inhibitors such as tubulin.
  • PublicationAccès libre
    Synthesis, biological evaluation and structure-activity relationships of novel substituted N-phenyl ureidobenzenesulfonate derivatives blocking cell cycle progression in S-phase and inducing DNA double-strand breaks
    (American Chemical Society, 2012-07-13) Fortin, Sébastien; Masson, Jean-Yves; Vevey, Florence; Turcotte, Vanessa; Côté, Marie-France; Lacroix, Jacques M.; Coulombe, Yan.; C. Gaudreault, René.
    Twenty-eight new substituted N-phenyl ureidobenzenesulfonate (PUB-SO) and 18 N-phenylureidobenzenesulfonamide (PUB-SA) derivatives were prepared. Several PUB-SOs exhibited antiproliferative activity at the micromolar level against the HT-29, M21, and MCF-7 cell lines and blocked cell cycle progression in S-phase similarly to cisplatin. In addition, PUB-SOs induced histone H2AX (γH2AX) phosphorylation, indicating that these molecules induce DNA double-strand breaks. In contrast, PUB-SAs were less active than PUB-SOs and did not block cell cycle progression in S-phase. Finally, PUB-SOs 4 and 46 exhibited potent antitumor activity in HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membranes, which was similar to cisplatin and combretastatin A-4 and without significant toxicity toward chick embryos. These new compounds are members of a promising new class of anticancer agents.
  • PublicationAccès libre
    N-Phenyl-N′-(2-chloroethyl)ureas (CEU) as potential antineoplastic agents. Part 2 : role of ω-hydroxyl group in the covalent binding to β-tubulin
    (Oxford Pergamon, 2006-11-10) Fortin, Sébastien; Rousseau, Jean; Desjardins, Michel; C. Gaudreault, René.; Patenaude, Alexandre.; Moreau, Emmanuel
    Tubulin is the target of many anticancer drugs, including N-phenyl-N′-(2-chloroethyl)urea (CEU). Unlike most anti-β-tubulin agents, CEUs are protein monoalkylating agents binding through their N′-(2-chloroethyl)urea moiety to an amino acid nearby the colchicine-binding site on β-tubulin isoform-2. Following the previously synthesized and attractive N-(3-ω-hydroxyalkylphenyl)-N′-(2-chloroethyl)urea that exhibited growth inhibitory activity at the nanomolar level, we investigated the importance of lower alkyl and alkoxy groups to evaluate the effect of hydroxylated group and chain length on both cell growth inhibition and the mechanism of action of CEU. Here, we describe the preparation of two new series of CEU and show that the most potent CEU derivatives beside the ω-hydroxylated 1f were 2f and 3e, respectively. We have confirmed that the pentyl substituted CEUs 1f, 2f, and 3e are still covalently binding to β-tubulin and still arrest cell division in G2/M phase.