Personne : 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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ncf13678332
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- PublicationAccès libreInhibitory effects of cytoskeleton disrupting drugs and GDP-locked Rab mutants on bradykinin B2 receptor cycling(Academic Press, 2013-05-01) Fortin, Sébastien; Roy, Caroline; Marceau, François; Lodge, Robert; Gera, Lajos; C. Gaudreault, René.; Charest-Morin, XavierThe bradykinin (BK) B2 receptor (B2R) is G protein coupled and phosphorylated upon agonist stimulation; its endocytosis and recycling are documented. We assessed the effect of drugs that affect the cytoskeleton on B2R cycling. These drugs were targeted to tubulin (paclitaxel, or the novel combretastatin A-4 mimetic 3,4,5-trimethoxyphenyl-4-(2-oxoimidazolidin-1-yl)benzenesulfonate [IMZ-602]) and actin (cytochalasin D). Tubulin ligands did not alter agonist-induced receptor endocytosis, as shown using antibodies reactive with myc-tagged B2Rs (microscopy, cytofluorometry), but rather reduced the progression of the ligand–receptor–β-arrestin complex from the cell periphery to the interior. The 3 fluorescent probes of this complex (B2R-green fluorescent protein [B2R-GFP], the fluorescent agonist fluorescein-5-thiocarbamoyl-D-Arg-[Hyp3, Igl5, Oic7, Igl8]-BK and β-arrestin2–GFP) were condensed in punctuate structures that remained close to the cell surface in the presence of IMZ-602. Cytochalasin D selectively inhibited the recycling of endocytosed B2R-GFP (B2R-GFP imaging, [3H]BK binding). Dominant negative (GDP-locked)-Rab5 and -Rab11 reproduced the effects of inhibitors of tubulin and actin, respectively, on the cycling of B2R-GFP. GDP-locked-Rab4 also inhibited B2R-GFP recycling to the cell surface. Consistent with the displacement of cargo along specific cytoskeletal elements, Rab5-associated progression of the endocytosed BK B2R follows microtubules toward their (−) end, while its recycling progresses along actin fibers to the cell surface. However, tubulin ligands do not suppress the tested desensitization or resensitization mechanisms of the B2R
- PublicationAccès libreStyryl-N-phenyl-N'-(2-chloroethyl)ureas and styrylphenylimidazolidin-2-ones as new potent microtubule-disrupting agents using combretastatin A-4 as model(Edifor, 2015-05-28) Fortin, Sébastien; Côté, Marie-France; Gagné-Boulet, Mathieu; Lacroix, Jacques M.; Lefebvre, Carole-Anne; C. Gaudreault, René.Combretastatin A-4 (CA-4) is a well-studied and attractive molecular template to develop new antimitotics. Several thousand of modifications were performed on the ring B and the ethenyl bridge of CA-4 but only a few involved the trimethoxyphenyl moiety (TMP, ring A) often considered essential to the antiproliferative and antimicrotubule activities. In this study, we described the design, the preparation, the characterization and the biological evaluation of three new series of CA-4 analogs namely styryl-N-phenyl-N'-ethylureas (SEUs), styryl-N-phenyl-N'-(2-chloroethyl)ureas (SCEUs) and styrylphenylimidazolidin-2-ones (SIMZs) bearing a 3-Cl (series a), 3,5-Me (series b) and TMP (series c) substituents, respectively. All SCEU and SIMZ Z-isomers were active in the high and the low nanomolar range, respectively. Conversely to SEUs and their E-isomers that were significantly less active or inactive. Interestingly, the TMP moiety is giving rise to derivatives exhibiting the lowest antiproliferative activity in the SCEU series (10c) and the most active compound in the SIMZ series (12c). Moreover, SIMZ Z-isomers bearing either a 3-Cl (12a) or a 3,5-Me (12b) exhibited antiproliferative activities that are also in the same order of magnitude as 12c. All SCEU and SIMZ Z-isomers also arrested the cell cycle progression in G2/M phase, bound to the colchicine-binding site and disrupted the cytoskeleton of cancer cells. In addition to the promising and innovative microtubule-disrupting properties of SCEUs and SIMZs, these results show that the TMP moiety is not essential for the cytocidal activity of these new CA-4 analogs.
- PublicationAccès libreN-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, EmmanuelTubulin 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.
- PublicationAccès libre4-(3-Alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides as new antimitotic prodrugs activated by cytochrome P450 1A1 in breast cancer cells(Elsevier, 2018-09-04) Chavez Alvarez, Atziri Corin; Zarifi Khosroshahi, Mitra; Fortin, Sébastien; Côté, Marie-France; Gagné-Boulet, MathieuThe role and the importance of the sulfonate moiety in phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were assessed using its bioisosteric sulfonamide equivalent leading to new cytochrome P450 1A1 (CYP1A1)-activated prodrugs designated as 4-(3-alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides (PAIB-SAs). PAIB-SAs are active in the submicromolar to low micromolar range showing selectivity toward CYP1A1-expressing MCF7 cells as compared to cells devoid of CYP1A1 activity such as MDA-MB-231 and HaCaT cells. The most potent, PAIB-SA 13, bearing a trimethoxyphenyl group on ring B blocks the cell cycle progression in G2/M phase, disrupts the microtubule dynamics and is biotransformed by CYP1A1 into CEU-638, its potent antimicrotuble counterpart. Structure-activity relationships related to PAIB-SOs and PAIB-SAs evidenced that PAIB-SOs and PAIB-SAs are true bioisosteric equivalents fully and selectively activatable by CYP1A-expressing cells into potent antimitotics.
- PublicationAccès libreMechanism 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 libreDiversity‐oriented synthesis of diol‐based peptidomimetics as potential HIV protease inhibitors and antitumor agents(Wiley, 2018-06-02) Fortin, Sébastien; Bouzriba, Chahrazed; Vadhadiya, Paresh M.; Jean, Marc Alexandre; Tremblay, Thomas; Lagüe, Patrick; Giguère, Denis; Boukouvalas, JohnPeptidomimetic HIV protease inhibitors are an important class of drugs used in the treatment of AIDS. The synthesis of a new type of diol-based peptidomimetics is described. Our route is flexible, uses d-glucal as an inexpensive starting material, and makes minimal use of protection/deprotection cycles. Binding affinities from molecular docking simulations suggest that these compounds are potential inhibitors of HIV protease. Moreover, the antiproliferative activities of compounds 33 a, 35 a, and 35 b on HT-29, M21, and MCF7 cancer cell lines are in the low micromolar range. The results provide a platform that could facilitate the development of medically relevant asymmetrical diol-based peptidomimetics
- PublicationAccès libreN-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, Emmanueln 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.
- PublicationAccès libreModélisation moléculaire, synthèse chimique, évaluation de l'activité antiproliférative et détermination du mécanisme d'action de nouveaux dérivés d'arylchloroéthylurées hybrides et de 2-imidazolidones(2010) Fortin, Sébastien; C. Gaudreault, René.; Moreau, Emmanuel; Teulade, Jean-ClaudeLe cancer est une maladie complexe qui tue des milliers de personnes chaque année. De nouveaux traitements sont donc en demande constante. Dans ce contexte, notre laboratoire développe de nouveaux agents anticancéreux nommés N-phényl-N'-(2-chloroéthyl)urées ou arylchloroéthylurées (CEU). Les travaux que j'ai réalisés au doctorat avaient pour objectif initial d'étudier les mécanismes d'action des CEU classiques afin de préciser les éléments structuraux clés, conduisant à l'acylation de l'acide glutamique en position 198 de la β-tubulin (Glul98). C'est dans ce cadre que mes travaux au doctorat ont débuté par des études en modélisation moléculaire et en spectrométrie de masse (MS) conduisant à l'élaboration de nouveaux modèles moléculaires d'interactions survenant entre les CEU et la tubuline permettant ainsi d'affiner nos connaissances du mécanisme d'action des CEU. La conception de ces nouveaux dérivés CEU édifiés sur la base de nos modèles moléculaires a permis de mieux connaître et de définir de nouveaux aspects structuraux des CEU tels que: (1) confirmer la présence essentielle du groupement haptophore 2-chloroéthylurée dans le but d'une acylation de Glul98 et à la sélectivité des CEU vis-à-vis la P-tubuline, (2) définir le groupement N-phényl-N'-(2-chloroéthyl)urée comme un pharmacophore mimant approximativement le groupement triméthoxylé de la colchicine et de la combrétastatine A-4 (CA-4), (3) confirmer que le groupement éthenyle du système stilbènique peut aussi être remplacé par un groupement sulfonate en conservant l'activité antiproliferative mais en perdant la sélectivité vis-à-vis la β-tubuline et (4) concevoir et évaluer biologiquement des dérivés nommés diphénylsulfonate 2-imidazolidones (DPS-IMZ). Ces derniers ont un pouvoir antiprolifératif de 100 à 1000 fois plus élevé que les CEU dites « classiques ». Les DPS-IMZ sont des agents antimicrotubules non acylants. Elles ont une activité pharmacologique comparable à celle de la combrétastatine A-4 et présentent plusieurs avantages par rapport à cette dernière étudiée en clinique. Elles sont simples à synthétiser, peu onéreuses à préparer et elles sont surtout chimiquement plus stables car elles sont dépourvues de groupement stilbènique. Plusieurs dérivés DPS-IMZ ont une activité antinéoplasique élevée dans le modèle tumoral de la membrane chorio-allantoïdienne (CAM) chez l'embryon de poulet et ils montrent peu ou pas de toxicité. Les DPS-IMZ sont donc une nouvelle classe d'agents anticancéreux prometteurs.
- PublicationAccès libreSubstituted 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 libreIntramolecular 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, FrançoiseThe 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.