Abstract
The development of anticancer compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs) is a promising research area for pharmaceutical companies and research institutes. A series of 3,5-disubstituted 1,2,4-oxadiazoles, sharing common structural features with colchicine and combretastatins, was designed and synthesized for screening as antiproliferative CBSIs. All targets were submitted to National Cancer Institute (NCI), USA for screening at 10 mM in full NCI 60 cell panel. In addition, molecular docking studies were performed for the newly synthesized oxadiazole derivatives as CBSIs in beta-tubulin against the beta-tubulin pocket of colchicine. Also, 5a - as the most active member - was evaluated for its ability to inhibit beta-tubulin polymerization against colchicine 6 as a reference standard. The targets showed significant antiproliferative activities. Amongst the series, target 5a demonstrated the broadest and most potent antiproliferative activity (positive cytotoxic effect (PCE) = 33/60 and the mean growth inhibition (MGI) for the most sensitive cell lines (33) is 24.9%. In addition, targets (5a-k) showed selective potency towards renal cancer in particular the A498 cell line. The order of potency of the three most potent targets and the standard colchicine (retrieved from NCI database) against A498 is: colchicine (GI = 84.5%) > 5a (GI = 78%) > 5d (GI = 51%) > 5f (32%). Compound 5a achieved superior binding affinity (-8.06 kcal mol(-1)) compared with that of colchicine 6 itself, which achieved (-7.40 kcal mol(-1)). Also, 5a showed a two-fold potent inhibitory activity of tubulin polymerization (IC50: 1.18 mu M) compared with that of colchicine (IC50: 2.37 mu M). Thus, target 5a represents a promising selective anticancer CBSI.