Personne : Biron, Éric
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Université Laval. Faculté de pharmacie
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- PublicationAccès libreToward solid-phase peptide fragment ligation by a traceless-Ugi multicomponent reaction approach(Royal Society of Chemistry, 2016-11-14) Biron, Éric; Jobin, Steve; Galindo, Sindy-Marcela; Vézina-Dawod, Simon; Fontaine, Alexia; Liang, XinxiaA new methodology to couple peptide fragments on solid support using a traceless isocyanide-based multicomponent reaction is described. The approach uses a microwave-assisted on-resin Ugi four-component reaction to attach a carboxyl free peptide to a supported peptide bearing a free N-terminal amine via the formation of an N-protected amide bond at the ligation site. Afterward, the generated backbone amide protecting group can be efficiently removed by microwave-assisted acidolysis with trifluoroacetic acid to afford a fully deprotected peptide. This straightforward Ugi reaction/deprotection approach was applied to condense various fragment lengths and provided a variety of oligopeptides.
- PublicationAccès librePreparation of N-substituted N-arylsulfonylglycines and their use in peptoid synthesis(American Chemical Society, 2015-11-09) Biron, Éric; Jobin, Steve; Herby, Claire; Vézina-Dawod, Simon; Derson, AntoineTo increase the chemical diversity accessible with peptoids and peptide–peptoid hybrids, N-alkylated arylsulfonamides were used to prepare side chain protected N-substituted glycines compatible with solid-phase synthesis. The described procedures give access to peptoid monomers bearing a wide variety of functional groups from commercially available amines in four straightforward steps. The prepared N-substituted N-arylsulfonylglycines were used as monomers in solid-phase synthesis to introduce relevant functionalized side chains into peptoid oligomers and peptide–peptoid hybrids.
- PublicationAccès libreN-Substituted arylsulfonamide building blocks as alternative submonomers for peptoid synthesis(Elsevier, 2015-01-08) Biron, Éric; Derson, Antoine; Vézina-Dawod, SimonPeptoids (oligo N-substituted glycines) are peptidomimetic oligomers showing attractive structural and pharmacological properties. The efficiency of their synthesis has prompted the use of peptoids in combinatorial libraries. To increase the chemical diversity accessible in peptoid design and libraries, we demonstrate here that N-substituted o-nitrobenzenesulfonamide derivatives can be used as alternative building blocks in the synthesis of peptoids by the submonomer approach. The preparation of N,O-protected amino alcohol submonomers and the conditions for their incorporation into peptoid oligomers are reported. The described method is compatible with the submonomer approach and was applied to prepare peptoid oligomers bearing different hydroxylated side chains.
- PublicationAccès libreConvenient two-step synthesis of highly functionalized benzo-fused 1,4-diazepin-3-ones and 1,5-diazocin-4-ones by sequential Ugi and intramolecular SNAr reactions(Pergamon Press, 2017-09-18) Biron, Éric; Vézina-Dawod, Simon; Liang, Xinxia; Gerber, NicolasBenzodiazepinones are an important family of heterocycles with very attractive pharmacological properties and peptidomimetic abilities. We report herein a rapid and efficient two-step synthesis of polysubstituted 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones using a multicomponent condensation/cyclization strategy. The approach uses an Ugi four-component reaction to condense readily available Nα-Fmoc-amino acids, amines and isocyanides with a 2-fluorobenzaldehyde derivative followed by a one-pot Fmoc-group removal, intramolecular aromatic nucleophilic substitution for ring closure and side chain deprotection. The described method gives access to benzo-fused 7- and 8-membered rings bearing a wide variety of functionalized substituents and was applied to efficiently prepare tri- and tetrasubstituted 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones in high yields in two straightforward steps.
- PublicationRestreintSynthetic Strategies for Macrocyclic Peptides(John Wiley & Sons, 2017-08-18) Biron, Éric; Vézina-Dawod, Simon; Bédard, FrançoisPeptide macrocycles form an outstanding class of natural and synthetic bioactive compounds. This chapter discusses synthetic strategies for the final ring‐closing reaction by the widely employed and versatile processes of lactamization, lactonization, and disulfide bridge formation. According to the nature of the chemical bond found in the backbone, cyclic peptides can be classified in two major categories: homodetic peptides and heterodetic peptides. In principle, all methods suitable for peptide bond formation can be applied for head‐to‐tail macrocyclization of linear peptides; however the reaction usually proceeds more slowly than the corresponding bimolecular version. During synthesis design, the C‐terminal amino acid of the linear precursor and the coupling reagent should be carefully chosen to minimize epimerization at the C‐terminal residue during cyclization. In many cases, the solution‐phase strategy is the best choice for performing the macrocyclization step, especially when larger quantities of cyclic peptide are required.
- PublicationAccès libreOne-pot photochemical ring-opening/cleavage approach for the synthesis and decoding of cyclic peptide libraries(American Chemical Society, 2016-02-25) Biron, Éric; Porte, Karine; Vézina-Dawod, Simon; Bédard, François; Liang, XinxiaA novel dual ring-opening/cleavage strategy to determine the sequence of cyclic peptides from one bead, one compound libraries is described. The approach uses a photolabile residue within the macrocycle and as a linker to allow a simultaneous ring opening and cleavage from the beads upon UV irradiation and provide linearized molecules. Cyclic peptides of five to nine residues were synthesized and the generated linear peptides successfully sequenced by tandem mass spectrometry.
- PublicationRestriction temporaireSynthesis and biological evaluation of novel 1,4-benzodiazepin-3-one derivatives as potential antitumor agents against prostate cancer(Pergamon, 2021-07-21) Biron, Éric; Gobeil, Stéphane; Vézina-Dawod, Simon; Gerber, Nicolas; Guay, Louis-David; Perreault, MartinA novel tumor suppressing agent was discovered against PC-3 prostate cancer cells from the screening of a 1,4-benzodiazepin-3-one library. In this study, 96 highly diversified 2,4,5- trisubstituted 1,4-benzodiazepin-3-one derivatives were prepared by a two-step approach using sequential Ugi multicomponent reaction and simultaneous deprotection and cyclization to afford pure compounds bearing a wide variety of substituents. The most promising compound showed a potent and selective antiproliferative activity against prostate cancer cell line PC-3 (GI₅₀ = 10.2 µM), but had no effect on LNCAP, LAPC4 and DU145 cell lines. The compound was initially prepared as a mixture of two diastereomers and after their separation by HPLC, similar antiproliferative activities against PC-3 cells were observed for both diastereomers (2S,5S: GI₅₀ = 10.8 µM and 2S,5R: GI₅₀ = 7.0 µM). Additionally, both diastereomers showed comparable stability profiles after incubation with human liver microsomes. Finally, in vivo evaluation of the hit compound with the chick chorioallantoïc membrane xenograft assay revealed a good toxicity profile and significant antitumor activity after intravenous injection.