Design, synthesis, docking study and anticancer evaluation of new trimethoxyphenyl pyridine derivatives as tubulin inhibitors and apoptosis inducers

Abstract

Microtubules have become an appealing target for anticancer drug development including mainly colchicine binding site inhibitors (CBSIs). A new series of novel trimethoxypyridine derivatives were designed and synthesized as tubulin targeting agents.In vitroanti-proliferative activities of the tested compounds compared to colchicine against hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116), and breast cancer (MCF-7) was carried out. Most of compounds showed significant cytotoxic activities. CompoundsVb,Vc,Vf,VjandVIshowed superior anti-proliferative activities to colchicine. Where compoundVIshowed IC50values of 4.83, 3.25 and 6.11 μM compared to colchicine (7.40, 9.32, 10.41 μM) against HCT 116, HepG-2 and MCF-7, respectively. The enzymatic activity against tubulin enzyme was carried out for the compounds that showed high anti-proliferative activity. Also, compoundVIexhibited the highest tubulin polymerization inhibitory effect with an IC50value of 8.92 nM compared to colchicine (IC50value = 9.85 nM). CompoundsVb,Vc,Vf,Vj, &VIIIbshowed promising activities with IC50values of 22.41, 17.64, 20.39, 10.75, 31.86 nM, respectively. Cell cycle and apoptosis test for compoundVIagainst HepG-2 cells, indicated that compoundVIcan arrest cell cycle at G2/M phase, and can cause apoptosis at pre-G1 phase, with high apoptotic effect 18.53%. Molecular docking studies of the designed compounds confirmed the essential hydrogen bonding withCYS241beside the hydrophobic interaction at the binding site compared to reference compounds which assisted in the prediction of the structure requirements for the detected antitumor activity.