Novel Gomisin B analogues as potential cytotoxic agents: Design, synthesis, biological evaluation and docking studies

摘要

Abstract As part of pharmacological-phytochemical integrated studies on medicinal flora, Gomisin B ( 1 ) was isolated as major phytochemical lead from schisandra grandiflora , a plant traditionally used in different Asian systems of medicine. A series of 1,2,3-triazoles derivatives were synthesized at the C-7′ position of the gomisin B core through diastereoselective Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reactions. All these triazolyl derivatives ( 5a - 5q ) were well characterized using modern spectroscopic techniques and evaluated for their anti-cancer activity against a panel of five human cancerous cell-lines. Among them, compound 5b exhibited the best cytotoxicity against SIHA cell (IC 50 0.24?μM) which was more than the standard drug doxorubicin, while the other derivatives were exhibited moderate to low activities in tested cell lines. The cell cycle analysis indicated that compound 5b stalled HeLa cells at G2/M phase. 5b promoted tubulin polymerization and this was supported by the docking studies, wherein 5b showed significant binding affinity at the colchicine binding pocket of tubulin. Overall, we identified a novel small molecule that demonstrated anticancer activity by promoting in?vitro tubulin assembly. Graphical abstract A series of 1, 2,3-triazoles derivatives were synthesized at the C-7′ position of the gomisin B core through click protocol. Among them, cell cycle analysis indicated that compound 5b caused a cell cycle arrest of HeLa cells at G2/M phase and also promoted tubulin polymerization, similar to Paclitaxel. Overall, we identified a novel small molecule that demonstrated anticancer activity by promoting in?vivo tubulin assembly. Display Omitted Highlights ? Novel Gomisin B analogues were synthesized and tested against cancer cell lines. ? Among the derivatives, 5b showed potent cytotoxic activity against SIHA cell line. ? 5b caused cell cycle arrest at G2/M phase and inhibited tubulin polymerization. ? Docking studies showed significant binding affinity at colchicine binding pocket.