Synthesis And Biological Study Ofnovel Imidazo[1,2-a]Pyridine Analogs Asmicrotubuleinhibitors With Anticancer Activity

In this research,we summarized the current situation of cancer incidence and treatment strategies,and summarized the current clinical application of anticancer drugs.As a promising target,the study of tubulin inhibitors has attracted the attention of many pharmaceutical scientists.However,most of the natural tubulin inhibitors currently used in clinical practice are prone to form drug resistance and poor water solubility.Therefore,the development of new tubulin inhibitors based on Colchicine sites has a better prospect.On the basics of our previous work,we designed and synthesized a series of derivatives with imidazole[1,2-a]pyridine as the mother nucleus through the strategy of ring fusion and bioelectronic rearrangement,and evaluated their biological activities in vitro.Fortunately,some of the molecules we synthesized showed strong antiproliferative activity on Jurkat,B16-F10,HCT116,and MDA-MB231 tumor cell lines(IC50 values ranged from micromolar to nanomolar).Among them,5b has the best anti-proliferative activity on Jurkat,B16-F10,HCT116 and MDA-MB231 cells,with IC50 values of 60 nM,380 nM,138 nM and 1.054 μM respectively.In vitro cell wound healing assay showed that 5b were able to inhibit the migration of B16-F10 cells strongly.In addition,5b effectively inhibited the growth of B16-F10 cell community units in the cancer colony formation assay,especially when the concentration of 5b reached 5 μM.Furthermore,we analyzed the effect of compound 5b on the cycle and apoptosis of B16-F10 cells via flow cytometry.It is exciting to find that 5b can induce B16-F10 cell apoptosis(including early apoptosis and late apoptosis)and arrest cell cycle in G2/M phase in a concentration-dependent manner in cell apoptosis test and cell cycle test,respectively.The result of tubulin polymerization assay also indicated that 5b functions its anticancer acitivity via inhibiting the tubulin polymerization.The results of molecular docking simulation experiments also showed that 5b effectively bound to the Colchicine site of tubulin and the docking pose was similar to that of CA-4.We also analyzed the water solubility of 5b,but the water solubility of 5b still needs to be improved.To sum up,compound 5b is considered a promising tubulin inhibitor,which is worthy of our further investigation.