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

As the second leading killer of human health,the number of cancer patients is increasing year by year.Although researchers have developed a variety of treatments for cancer(chemotherapy,radiotherapy and induced therapy),there is still a long way for humans to go before they can defeat cancer.In order to conquer malignant tumor,pharmaceutical chemists have found different kinds of chemotherapy drugs;some of which show significant therapeutic effect.However,the side reaction and resistance still remain confusing pharmaceutical chemists like a curse.Apoptosis escaping is an important approach which contribute to drug resistance.The abnormal expression of Bcl-2 proteins family is responsible for cell Apoptosis escaping as crucial regulators.Several anti-apoptosis protein like Bcl-2,Mcl-1 and Bcl-XL show over expression in various cancer cells.As a result,the idea of prohibition of Bcl-2 anti-apoptosis becomes an important research direction.Based on relevant study results our research group had gained in recent years and referring to some relevant studies of international peers,we have designed and synthesized two series of indole-3-acetic acid derivatives as Bcl-2 proteins inhibitors containing 29 new structures.All objective compounds have been confirmed using 1H-NMR,13C-NMR and HRMS.Then we utilize FPAs and MTT to evaluate their activity of the protein prohibiting and anti-proliferation on tumor cells respectively.The good news is that we have selected several molecules,whose activity is better than the activity of the positive matched group.Objective compounds 9c,9d,9h and 10b show dual inhibition activity,which is better than Bcl-2/Mcl-1 of WL-276.Moreover,they also show stronger anti-proliferative activities against tumor cell lines.At the same time,the four objective compounds mentioned above do not show significant prohibition to Bcl-XL protein.It is likely that they can be used avoiding side effects like reduction of platelet.9h show the most balanced prohibition activity of Bcl-2/Mcl-l and the strongest activity of anti-proliferation on tumor cells.This study lays foundation for the exploitation of Bcl-2/Mcl-1 dual inhibitors with subtype selective ability.