The Design, Synthesis, In Vitro Biological Evaluation And Molecular Modeling Of Novel Indole Derivatives Bearing Sulfonamide And Piperazidine Moieties As Potent Anti-microtubulin Polymerization Agents

Microtubules, as a main component of spindle, play an important role in the process of mitosis. However, the abnormal expression of some proteins associated to microtubule in tumor cells makes the process of cell mitosis frequent, which caused disorde of cell cycle and uncontrolled growth of cancer cells. Thus it can be seen that microtubulin plays an important role in developing cancer. So if the microtubules dynamic circulation was disrupted, the formation of spindle can be blocked, the cell mitotic will be disrupted,which can induce cell cycle arrest and apoptosis,thus achieve the purpose of anti tumor. Therefore, tubulin has gradually become one of the important targets in pharmaceutical research and development of anticancer drugs, and inhibitors targeting microtubule has become clinically proven effective anti-tumor drugs.Indole derivatives, a kind of a large class of compounds containing benzo five member heterocyclic struture, were proved with anti-tumor activity, antibacteria and antiviral activity, lowering blood pressure, antiemetic,and antiinflammatory activity. hence, they raise increasing focuses in drug discovery. The studies regarding mechanism of antitumor showed that the indole analogue inhibit or promote the polymerization of tubulin to interfere with the mitosis of the cell and thus to achieve the effect of anti-tumor. Meanwhile, sulfonamide and piperazine also play significant roles in anti-tumor drugs’research, for their exceptionally various biological activities. Based on the remarkable biological activity indole, sulfonamide and piperazine analogue, we designed and synthesized a novel series of indole analogues bearing sulfonamide and piperazine moiety as microtubulin polymerization inhibitors.We have used the Ligand Fit Dock protocol of Discovery Studio to screen quantities of indole derivatives containing sulfonamide and piperazine scaffolds.A series of novel compounds (7-30) bearing sulfonamide skeleton and piperazine moiety has been synthesized and characterized by 1H NMR,13C-NMR, MS analysis. We have evaluated the biological activities for these compounds. As the results of proliferative inhibitory assay showed, compound 18 exhibited the most potent antiproliferative activity against HepG2、Hela、A549 and MCF-7 cancer cell lines with IC50 values of 0.49、0.24、0.35 and 0.59μM, respectively. Compound 18 also displayed significant tubulin polymerization inhibitory activity (IC50=1.82μM), which was superior to the positive control (colchicine). Moreover, we also demonstrated that compound 18 was a potent inducer of apoptosis in Hela cells and it also could cause accumulation of cells in the G2/M phase of the cell cycle. The immunofluorescence staining test indicated that compound 18 could inhibit microtubule polymerization. In addition, we performed molecular simulation to investigate the mode of action between tubulin and compound 18. The result revealed that compound 18 was nicely bound to the microtubule via a hydrogen bond and numerous intermolecular forces.