Design,Synthesis And Anti-tumor Activities Analysis Of Indole Amide Derivatives As Novel Histone Deacetylase Inhibitors

Cancer is one of the most leading cause of death in the world,second only to car-diovascular disease.Epigenetic regulation has been demonstrated to be associated with the genesis of cancer,it includes modification of DNA methylation,histone modifica-tion,chromatin remodeling,and mRNA gene silencing.Lots of research show that acet-ylation and deacetylation of histones play a vital role in biological processes.In normal condition in human body,keeping dynamic equilibrium of the histone acetyltransfer-ases(HATs)and the histone deacetylases(HDACs)is required to ensure that gene ex-pression and various physiological functions work normally.Recent years,many ex-periments have shown that HDACs are highly expressed in tumor cells.HDAC has been one of the most popular targets for targeted therapy.HDAC inhibitors can promote acetylation of histones and suppress tumor growth.So far,FDA has approved four HDAC inhibitors used for the treatment of non-solid tumors.Utilizing indole amide cap as the structural scaffold,we developed several hy-droxamic acid-based compounds whose structures are similar to SAHA and Tubastatin A while showing improved potency compared to SAHA.We investigated the im-portance of changing carbon chain lengths and incorporating different aromatic rings into the linker for improving potency of compounds.Besides,we introduced different types of substitutional groups into indole amide scaffold and explored the possibilities of simple chemical structural transformation of cap region.Through the analysis of structure-activity relationship,we obtained a series of small molecule compounds.Compared to SAHA,these new compounds display better potency in vitro enzymatic assays.Further experiments showed that compound 11d has antiproliferation and pro-apoptotic activity against majority human cancer cell lines.It was worth noting that compound 4d has an excellent HDAC6 selectivity compared to HDAC1.It laid the foundation for us to research selective HDAC6 inhibitors.