Design,Synthesis And Preliminary Biological Evaluation Of N-Arolyl-Indole-3-Acetic Acid Derivatives As New Bcl-2 Proteins Inhibitors

Cancer is a complicated process,which has the characteristics of abnormal cell differentiation,proliferation,uncontrol growth,infiltration and metastasis.Nowdays,cancer has become one of the common killers seriously threatening human health.At present,the treatment of cancer includes chemotherapy,radiotherapy,surgery and immunotherapy,in which there are still many limitations and side effects.So far,improving existing cancer treatments is the most important and challenging job for medical workers worldwide.Specially,scientists have discovered and designed a variety of small molecule chemotherapeutic drugs,which target specific proteins,for precise treatment of cancer.Because of the critical role of Bcl-2 protein family in cell apoptosis,small molecule compounds targeting anti-apoptotic Bcl-2 family proteins gained lots of research interests in the past two decades.In normal cells,Bcl-2 family proteins are involved in the regulation of normal cell apoptosis.In cancer cells,the expression of Bcl-2 protein family is abnormal,which results in apoptosis escape.Therefore,inhibiting Bcl-2 anti-apoptotic protein has become an important and effective anti-tumor strategy.Based on our previous study of Bcl-2 anti-apoptotic protein inhibitors as well as progress of related research field,a total of 39 new compounds were designed and synthesized as new Bcl-2 proteins inhibitors.New compounds include 10 intermediates and 29 target compounds with N-aroyl-indole-3-acetic scaffold.Chemical structures of all these target compounds were confirmed by 1H-NMR,13C-NMR and HRMS.Subsequently,Fluorescence Polarizationtion Assays(FPAs),MTT and Flow CytoMetry(FCM)methods were used to evaluate the Bcl-2 protein inhibitory activity,anti-proliferation activity and apoptosis inducing activity of target compounds.Importantly,several active compounds showed improved activities than that of the known Bcl-2 protein inhibitor WL-276.The target compounds 8h,8j,8k,81 and 8m showed better Bcl-2/Mcl-1 dual inhibitory activities as well as higher anti-proliferation activity than WL-276.In addition,the five target compounds showed slightly inhibitory activies on Bcl-XL protein,which would be helpful to avoid the side effect of thrombocytopenia caused by inhibiting Bcl-XL.In addition,compound 8j(Ki=0.44 ± 0.02?M for Bcl-2,Ki=0.44 ± 0.03?M for Mcl-1)showed best inhibiting activity on Bcl-2/Mcl-1 and possess anti-proliferation activity on tumor cells.This work provides a good starting point to explore isoform-selective inhibitors of apoptotic Bcl-2 proteins.