Synthesis, Modelling, and Antimitotic Properties of Tricyclic Systems Characterised by a 2-(5-Phenyl-1H-pyrrol-3-yl)-1,3,4-oxadiazole Moiety

Interesting antitumor activity was observed in a series of tricyclic compounds characterized by the presence of a 2-(1H-pyrrol-3-yl)-1,3,4-oxadiazole moiety variously substituted. Their synthesis and their antiproliferative activity on a panel of human tumor cell lines is described. The most interesting compounds 1c and 4c were selected for further evaluation in order to understand their possible mechanism of action. Analysis of cell cycle, tubulin polymerization, modulation of mitotic markers of M phase and apoptosis showed that the antimitotic activity is the primary mechanism of their cytotoxic effects. The experiment performed on isolated tubulin confirm that the compounds act by inducing tubulin polymerization, like taxanes. The binding model against tubulin was also examined by molecular modeling and docking. The results point out that the proposed binding model is able to explain the oxadiazole derivatives activity on the basis of their docking energy