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Synthesis, modelling, and antimitotic properties of tricyclic systems characterised by a 2-(5-Phenyl-1H-pyrrol-3-yl)-1,3,4-oxadiazole moiety

Pinna, Gérard Aimé and Murineddu, Gabriele and Murruzzu, Caterina and Zuco, Valentina and Zunino, Franco and Cappelletti, Graziella and Artali, Roberto and Cignarella, Giorgio and Solano, Lucrezia and Villa, Stefania (2009) Synthesis, modelling, and antimitotic properties of tricyclic systems characterised by a 2-(5-Phenyl-1H-pyrrol-3-yl)-1,3,4-oxadiazole moiety. ChemMedChem, Vol. 4 (6), p. 998-1009. eISSN 1860-7187. Article.

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DOI: 10.1002/cmdc.200800428

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.

Item Type:Article
ID Code:7815
Status:Published
Refereed:Yes
Uncontrolled Keywords:Antitumor agents, cytotoxicity, molecular modeling, oxadiazoles, tubulin polymerisation
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze del farmaco
Publisher:Wiley
eISSN:1860-7187
Deposited On:24 Jul 2012 11:56

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