Process Improvement Of Belinostat And Development And Evaluation Of Novel Histone Deacetylase Inhibitors

Tumor is one of the most dangerous diseases threatening human health globally,and the epigenetic abnormity composes the major reasons of carcinogenesis.The regulation of epigenetic modification has become a kind of significant treatments of tumors.Regulation of the epigenetics,such as modification of histone proteins,which can be catalyzed by HDACs(histone deacetylases),has becom an important means to treat tumors.HDACs lead to the removal of acetyl groups of lysine residues of chromatin histones,allowing the chromatin more cohesive,making the histone proteins and DNA tightly coupled and finally leading to the repression of some tumor suppressor genes.Histone deacetylases inhibitors,which also called HDACIs are a series of small-molecule inhibitors which can inhibit the deacetylation of HDACs,are important methods for treating tumor and neurodegeneration diseases.At present,five drugs have been proved by FDA to treat tumors,such as vorinostat,romidepsin.belinostat,panobinostat,chidamide.There are eighteen different HDACs calssified into four sub-classes due to their different substructure,biofunctions and locations.Due to the various functions of HDACs in cell survival.HDACIs with isoform selectivity have become the hot topic in antitumor research.Belinostat can inhibit the broad spectrum of HDACs,particularly HDAC1,2,3.Due to its potent antitumor activity,belinostat has become the orphan drug of peripheral T cell lymphoma(PTCL).In the 2015.the saleroom of belinostat has doubled than last year(2014).which indicates the high economic value of belinostat and its synthetic study.In this paper,two new routes,in which the syntheses of compound 6 and belinostat has been put forward for first time under a mild reaction conditions without the using of Cr and oxalyl chloride.The total yield is around 18%based on at least three times determinations.Based on the former studies of our group and review of the literature,a series of novel N-hydroxybenzamide based HDACIs with various Caps have been designed and synthesized to investigate their anti-tumor activity,HDACs inhibitory activity as well as HDACs isoform selectivity.The study of HDACs inhibitory activity and isoform selectivity of these new compounds revealed that compounds 7a,7b,7c displayed higher HDAC8 selectivity than the positive control PXD101.Our compounds showed superior antiproliferative activity in Molt-4,SK-N-BE-2 and Jurkat cell lines than in other tumor cell lines(such as HEL K562),which proved the significance of HDAC8 selective inhibitors in antitumor application.This gave us enlightenment in the design of HDAC8 selective inhibitors as antitumor agents.