title: Synthesis, modelling, and antimitotic properties of tricyclic systems characterised by a 2-(5-Phenyl-1H-pyrrol-3-yl)-1,3,4-oxadiazole moiety.
abstract: Antitumour activity was observed in a series of tricyclic compounds characterised by a 2-(1H-pyrrol-3-yl)-1,3,4-oxadiazole moiety with various substitutions. Their synthesis and antiproliferative activity toward a panel of human tumour cell lines is described. The most interesting compounds 1 c and 4 c were selected for further evaluation to elucidate their possible mechanism of action.Interesting antitumour activity was observed in a series of tricyclic compounds characterised by the presence of a 2-(1H-pyrrol-3-yl)-1,3,4-oxadiazole moiety that is variously substituted. Their synthesis and antiproliferative activity toward a panel of human tumour cell lines is described. The two most interesting compounds were selected for further evaluation to elucidate their possible mechanism of action. Analysis of cell cycle, tubulin polymerisation, modulation of mitotic markers of the M phase, and apoptosis showed that antimitotic activity is the primary mechanism of the cytotoxic effects of these compounds. Experiments performed on isolated tubulin confirmed that the compounds act by inducing tubulin polymerisation, like taxanes. The binding model against tubulin was also examined by molecular modelling and docking. The results support the proposed binding model, which is able to explain the activity of the oxadiazole derivatives on the basis of their docking energy.
authors.affiliation: Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via F. Muroni 23, 07100 Sassari, Italy.
authors.forename: Gérard A
authors.initials: GA
authors.lastname: Pinna
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
authors.forename: Caterina
authors.initials: C
authors.lastname: Murruzzu
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
authors.forename: Graziella
authors.initials: G
authors.lastname: Cappelletti
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cignarella
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Solano
authors.forename: Stefania
authors.initials: S
authors.lastname: Villa
mesh_terms: D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: C542538:3-(1,3,4-oxadiazol-5-phenyl-2-yl)-1,4-dihydroindeno(1,2-b)pyrrole; C542539:3-(1,3,4-oxadiazol-5-phenyl-2-yl)-1H-benzo(g)indole; D050256:Antimitotic Agents; D015415:Biomarkers; D007192:Indenes; D007211:Indoles; D010069:Oxadiazoles; D011758:Pyrroles; D014404:Tubulin