Oxadiazole derivatives as a novel class of antimitotic agents: Synthesis, inhibition of tubulin polymerization, and activity in tumor cell lines

Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 μM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC50 = 7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure–activity relationships for this novel series of antimitotic agents.

The synthesis, SAR studies, and pharmacokinetic properties of oxadiazole based tubulin inhibitor class are reported. This class of compounds binds to the colchicine site on tubulin and has antimitotic activity with nanomolar potency against tumor cell lines including cells with MDR phenotype.Figure optionsDownload as PowerPoint slide