Design,Synthesis And Anti-tumor Activity Study Of Novel Histone Deacetylase Inhibitors Containing Isatin-based Caps And O-phenylenediamine-based Zinc Binding Groups

Cancer as a kind of disease threatening human beings’ health has displayed increasing morbidity and mortality in recent years.Developing new regimens for cancer treatment and anticancer agents has become a hot topic for researchers in biological and medicinal institutes worldwide.In recent decades,epigenetics has provided novel minds and opportunities for the exploration of mechanisms of oncogenesis and tumor therapies.According to the epigenetic hypothesis proved by more and more scientific evidences,cancer development and progression are associated with both genetic and epigenetic alterations.Steady-state levels of acetylation of the core histones result from the balance between the opposing activities of histone acetyltransferases(HATS)and histone deacetylases(HDACs),which is generally considered as a kind of epigenetic issue.In short,with the overexpression of HDACs,decreased levels of histone acetylation(hypoacetylation)can enrich the histone trails with positive charges,reinforcing the interactions between histones and DNA.The tightly compacted DNA is inaccessible for transcription factors to promoters,leading to the suppression of gene expression.Nevertheless,HATs have opposing functions.Eighteen different human HDAC isoforms have been described and can be divided into four classes based on structural homologies between human and yeast HDACs.Each HDAC has its own biological functions and most of them are involved in hematologic and solid malignancies.Therefore,HDACs have become new targets for the design and discovery of anticancer drugs.There are five HDACIs approved by FDA or CFDA as anticancer agents.Moreover,over 20 HDACIs entered different stages in clinic,most of which are pan-HDACIs.In the pioneering work of our lab,a series of pan-HDACIs showing promising anticancer effects have been designed and synthesized through introducing an endogenous compound named isatin which has various biological roles as fundamental scaffold.Scaffold splicing and hopping strategy was used to modify the lead compound 9a to afford a series of novel HDACIs with potent HD AC inhibitory activities and antitumor effects as well as high isoform-selectivity in this paper.Fortunately,by using several synthesized schemes,a novel series of HDACIs with isatin-based caps and o-phenylenediamine-based zinc binding groups have been obtained.In the biological evaluation,most compounds exhibited desired inhibition against HDACs,and among these compounds,the most potent compounds 9m and 9n exhibited similar if not better HDAC inhibition and antiproliferative activities against multiple tumor cell lines compared with the positive control entinostat(MS-275).As expected,5-substituted-o-phenylenediamine 23a exhibited dramatic HDAC 1/2 selectivity over HDAC3.It is worth noting that compared with MS-275,compound 9n exhibited moderate HDAC1 selectivity over HDAC2 and HDAC3.These results in this paper may lighten the way to explore creative isoform-selective HDACIs,especially exclusive HDAC1 inhibitors.