title: Synthesis of a 3-(α-styryl)benzo[b]-thiophene library via bromocyclization of alkynes and palladium-catalyzed to sylhydrazones cross-couplings: evaluation as antitubulin agents.
abstract: A library of functionalized 3-(α-styryl)-benzo[b]thiophenes, endowed with a high level of molecular diversity, was efficiently synthesized by applying a synthetic sequence that allowed introduction of various substituents on aromatic A, B, and C-rings. The strategy developed involves the synthesis of 3-bromobenzo[b]thiophene derivatives through a bromocyclization step of methylthio-containing alkynes using N-methylpyrrolidin-2-one hydrotribromide reagent (MPHT). Further coupling of 3-bromobenzothiophenes under palladium-catalysis with N-tosylhydrazones efficiently furnished 2-aryl-3-(α-styryl)benzo[b]thiophene derivatives. The antiproliferative properties of target compounds were studied. Among them, compound 5m has demonstrated submicromolar cytotoxic activity against HCT-116 cell line, and inhibited the polymerization of tubulin at micromolar level comparable to that of CA-4.
authors.affiliation: Univ Paris Sud, CNRS, BioCIS-UMR 8076 , Laboratoire de Chimie Thérapeutique, Equipe Labellisée Ligue Contre le Cancer, LabEx LERMIT, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France.
authors.forename: Bret
authors.initials: B
authors.lastname: Tréguier
authors.forename: Marie
authors.initials: M
authors.lastname: Lawson
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bernadat
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bignon
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Brion
authors.forename: Mouad
authors.initials: M
authors.lastname: Alami
authors.forename: Abdallah
authors.initials: A
authors.lastname: Hamze
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010165:Palladium / Q000737:chemistry; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000502:physiology*
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D006835:Hydrazones; D013343:Styrenes; D013876:Thiophenes; D014404:Tubulin; D010165:Palladium
keywords: N-tosylhydrazone; antimitotic agents; bromocyclization; migratory insertion; palladium; α-styrylbenzo[b]thiophene