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Personne :
Petitclerc, Éric

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Petitclerc

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Éric

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Département de microbiologie-infectiologie et d'immunologie, Faculté de médecine, Université Laval

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0000000075526788

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ncf11849043

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Voici les éléments 1 - 9 sur 9
  • 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
    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
    Substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides as antimitotics. Antiproliferative, antiangiogenic and antitumoral activity, and quantitative structure-activity relationships
    (2011-08-30) Fortin, Sébastien; Wei, Lianhu; Côté, Marie-France; Petitclerc, Éric; Lacroix, Jacques M.; C. Gaudreault, René.; Moreau, Emmanuel; Kotra, Lakshmi P.
    The importance of the bridge linking the two phenyl moieties of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) was assessed using a sulfonamide group, which is a bioisostere of sulfonate and ethenyl groups. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs exhibit antiproliferative activities at the nanomolar level against sixteen cancer cell lines, block the cell cycle progression in G2/M phase, leading to cytoskeleton disruption and anoikis. These results were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. These results evidence that the sulfonate and sulfonamide moieties are reciprocal bioisosteres and that phenylimidazolidin-2-one could mimic the trimethoxyphenyl moiety found in the structure of numerous potent antimicrotubule agents. Finally, compounds 16 and 17 exhibited potent antitumor and antiangiogenic activities on HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membrane similar to CA-4 without significant toxicity for the chick embryos, making this class of compounds a promising class of anticancer agents.
  • PublicationAccès libre
    Synthesis, antiproliferative activity evaluation and structure-activity relationships of novel aromatic urea and amide analogues of N-phenyl-N’-(2-chloroethyl)ureas
    (Elsevier Masson, 2010-03-25) Fortin, Sébastien; Côté, Marie-France; Petitclerc, Éric; Lacroix, Jacques M.; C. Gaudreault, René.; Moreau, Emmanuel
    Seven subsets of aromatic urea and amide analogues of N-phenyl-N0-(2-chloroethyl)ureas (CEU) have been synthesized by nucleophilic addition of 3-chloropropylisocyanate, 2-chloroacetylisocyanate, ethylisocyanate, 2-chloroacetyl chloride, 3-chloropropanoyl chloride, 4-chlorobutanoyl chloride, and acryloyl chloride, espectively, to selected anilines or benzylamines to afford 3-chloropropylureas (1, CPU), 2-chloroacetylureas (2, CAU), ethylureas (3, EU), 2-hloroacetamides (4, CA), 3-chloropropionamides (5, CPA), 4-chlorobutyramides (6, CBA) and acrylamides (7, cr). The molecular structure of these compounds has been confirmed by IR, 1H and 13C NMR, and MS spectra and their purity also confirmed by HPLC. The CEU analogues were evaluated for their antiproliferative activity against three human tumor cell lines, namely human colon carcinoma HT-29, human skin melanoma M21, and human breast carcinoma MCF-7. CAU (2c to 2g), CA (4a to 4d, 4f and 4g), CPA (5a) and Acr (7a and 7b) had IC50 ranging from 1.4 to 25 mM. CAU, CA, CPA and Acr exhibited interesting antiproliferative activity through mechanism(s) of action unrelated to the acylation of glutamic acid at position 198 on b-tubulin that is characterizing CEU.
  • PublicationAccès libre
    MMP-2 expression in uveal melanoma : differential activation status dictated by the cellular environment
    (2005-12-14) Guérin, Sylvain; Germain, Lucie; Bérubé, Mélanie; Petitclerc, Éric; Boucher, Maryse; Deschambeault, Alexandre
    MMPs are recognized to play a major role in tumor progression and metastasis of many forms of cancers. The purpose of this study was to compare the expression and activity of MMP-2 in uveal melanoma cell lines grown either in vitro on plastic culture plates or in vivo as tumors produced in chick embryos. The chick chorioallantoic membrane (CAM) model was used to evaluate the tumorigenic potential of uveal melanoma cell lines derived either from the primary uveal melanoma tumor isolated from three different patients (cell lines SP6.5, SP8.0, and TP31) or from a metastatic lesion derived from the liver of a patient diagnosed with uveal melanoma (cell line H79). The presence of MMP-2 in the vicinity of the tumor cells was determined by immunofluorescence analyses. Gelatin zymography was used for the detection of latent and activated forms of MMP-2 in uveal melanoma cell lines when grown in vitro on plastic, or in the solid tumors these cell lines produced in vivo on the CAM of the chick embryo. The gelatinase activity was quantified by densitometric analyses and the active/(active+pro-form) ratio was calculated as the MMP-2 activation ratio. Western blot analyses were performed to confirm the zymographic profile. Only the inactive form of MMP-2 was expressed and secreted in vitro by all uveal melanoma cell lines, higher levels being found for the liver-derived H79 cell line whereas SP8.0 only expressed MMP-2 to a very low level. On the other hand, all solid tumors produced in the CAM from these cell lines expressed and secreted, although to varying levels (SP6.5 and SP8.0, TP31 and H79), primarily the active form of MMP-2. Gelatinolytic activities of active MMP-2 were significantly higher in uveal melanoma tissues than in the non-neoplastic CAM, as revealed by the measurement of the activation ratio. The immunolocalization of MMP-2 revealed that all cell lines were MMP-2-positive although a reduced and more diffuse staining was observed for H79 and SP6.5 than in SP8.0 and TP31 cells. These results suggest the activation of proMMP-2 as an important event in the process of uveal melanoma progression. An elevated active to inactive MMP-2 ratio in the tumor environment of uveal melanoma suggests that a potential MMP-2 activity could be related to the progression of this type of cancer.
  • 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
    Vascular smooth muscle contractility assays for inflammatory and immunological mediators
    (Elsevier, 2010-09-08) Audet, Ritchie.; Deblois, Denis; Drapeau, Guy; Sabourin, Thierry; Bawolak, Marie-Thérèse; Koumbadinga, Gérémy Abdull; Fortin, Jean-Philippe.; Levesque, Luc; Marceau, François; Petitclerc, Éric; Morissette, Guillaume; Larrivée, Jean-François.; Godin, Denis; Gera, Lajos; Houle, Steeve.; Bouthillier, Johanne
    The blood vessels are one of the important target tissues for the mediators of inflammation and allergy; further cytokines affect them in a number of ways. We review the use of the isolated blood vessel mounted in organ baths as an important source of pharmacological information. While its use in the bioassay of vasoactive substances tends to be replaced with modern analytical techniques, contractility assays are effective to evaluate novel synthetic drugs, generating robust potency and selectivity data about agonists, partial agonists and competitive or insurmountable antagonists. For instance, the human umbilical vein has been used extensively to characterize ligands of the bradykinin B2 receptors. Isolated vascular segments are live tissues that are intensely reactive, notably with the regulated expression of gene products relevant for inflammation (e.g., the kinin B1 receptor and inducible nitric oxide synthase). Further, isolated vessels can be adapted as assays of unconventional proteins (cytokines such as interleukin-1, proteases of physiopathological importance, complement-derived anaphylatoxins and recombinant hemoglobin) and to the gene knockout technology. The well known cross-talks between different cell types, e.g., endothelium-muscle and nerve terminal-muscle, can be extended (smooth muscle cell interaction with resident or infiltrating leukocytes and tumor cells). Drug metabolism and distribution problems can be modeled in a useful manner using the organ bath technology, which, for all these reasons, opens a window on an intermediate level of complexity relative to cellular and molecular pharmacology on one hand, and in vivo studies on the other.
  • 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
    Role of the extracellular matrix proteins in the resistance of SP6.5 uveal melanoma cells toward cisplatin
    (Spandidos Publications, 2005-03-01) Paquet-Bouchard, Carine; Guérin, Sylvain; Germain, Lucie; Bérubé, Mélanie; Giroux-Talbot, Mariève; Petitclerc, Éric; Collin, Charles
    Uveal melanoma is the most frequent primary intraocular tumor in the adult population. This malignancy has a high mortality rate and responds poorly to existing chemotherapy. Recently, the tumor environment has been found to exert a profound influence on drug response through cell interaction with components from the extracellular matrix (ECM). In the present study, we investigated whether individual components from the ECM may affect cell survival and/or cell death induced by the cytotoxic agent cisplatin on the SP6.5 uveal melanoma cell line. Tumor cells were shown by immunofluorescence analyses to be surrounded by the ECM proteins fibronectin (FN), type IV collagen (CIV) and laminin (LM), both at the primary and metastatic sites. Binding of SP6.5 cells to FN, LM and CIV is primarily dictated by the expression of membrane bound integrins from the beta1 family as revealed by cell adhesion assays conducted on ECM-coated culture plates. Analysis of cell death by flow cytometry demonstrated that culturing SP6.5 cells in the presence of FN, CIV and LM, substantially reduced the percentage of cells undergoing apoptosis after cisplatin treatment when compared with those seeded on a non-permissive matrix. These results suggest that adhesion of the SP6.5 uveal melanoma cells to the ECM proteins FN, CIV and LM might therefore confer resistance to the chemotherapeutic agent cisplatin. The cellular resistance induced by the ECM proteins toward cisplatin could explain in part the local recurrence of metastasis derived from uveal melanoma often observed clinically after chemotherapy.