Design, Synthesis, Biological Evaluation And Molecular Modeling Of Combretastatin-A4Analogs As Novel Antitubulin Agents

Human cancer is one of difficult diseases to deal with. Drug therapy, as one of the primary treatment means, improves rapidly in recent years. The hot spot of the anti-cancer drug moves from Traditional cytotoxic drugs to drugs targetting cancer development, such as cellular signal transduction DNA, cytoskeleton and microtubules.Microtubules is the tubular structure, the fibrils parallel from end to end of the12to14connected, ubiquitous in the cytoplasm. The study shows that there are a large number of natural and synthetic compounds can interfere with tubulin function, with the role of microtubules, inhibiting its polymerization, the spindle can not form, thereby halting cell division in the mitotic metaphase; or promote microtubule polymerization inhibited depolymerization affect cell division. Tubulin active inhibitor is one of the most effective anti-cancer drugs.As an fundamental class of heterocyclic compounds,1,3,4-oxadiazoles possess a variety of bioactivity. Remarkably, a few differently substituted1,3,4-oxadiazoles have been found to exhibit anticancer activities which establishes this moiety as a member of the privileged structures class in pharmaceutical fields.A total of20novel1,3,4-oxadiazoline analogs (6a-6t) of combretastatin A-4with naphthalene ring were designed, synthesized, and evaluated for biological activities as potential tubulin polymerization inhibitors. Among these compounds,6i and6n showed the most potent antiproliferative activities against multiple cancer cell lines and retained the microtubule disrupting effects. Docking simulation was performed to insert compounds into the crystal structure of tubulin to determine the probable binding model and the QSAR model was built for reasonable design of tubuline inhibitors. These results showed oxadiazoline compounds bearing the naphthyl moiety are promising tubulin inhibitors.