Design,Synthesis And Biological Activity Of Novel N-(6-((2-hydroxypropyl)amino)-6-oxohexyl)Benzamides As HDAC Inhibitors

Histone deacetylases（HDACs）are currently a popular anti-tumor drug target.Currently,six histone deacetylase inhibitors have been approved for marketing.This type of HDAC inhibitor has a classical three-stage structure with a surface recognition zone（Cap）,zinc ion binding group（ZBG）and linker（Linker）.Among them,the hydroxamic acid structure is the most representative of the HDAC inhibitor of the zinc ion-binding group,but such compounds are poor in stability in vivo,easily metabolizedand highly toxic to normal cells.So we based on the structure of SAHA,with the hydroxamic acid group as a new zinc ion-binding group,and various substituent groups were introduced at the Cap.This study designed and synthesized SixteenN-（6-（（2-hydroxypropyl）amino）-6-oxohexyl）benzamidecompounds.These compounds were evaluated for in vitro cell viability.The specific research contents are as follows:（1）Evaluation of anti-cell proliferation activity of target compounds（MTT assay）,we determined the inhibitory activities of 16 compounds against three tumor cell lines（HeLa,HepG-2,A549）and one normal cell line（WI-38）.These compounds were found to be sensitive to HeLa cell lines(IC₅₀=19.93⁷7.06μM),and compounds a6(IC₅₀=24.22±0.19μM)and a9(IC₅₀=19.93±0.58μM)were the best;（2）HDAC enzyme,The activity evaluation showed that the compounds a6 and a9 had good inhibitory activity against HDAC,IC₅₀ values were 34.3±3.25μM,22.5±2.84μM;（3）Effects of compounds a6 and a9 on the expression of HDAC-related proteins,WB experiment The results showed that a6 could increase the expression of Ac-tubulin in cells,and a9 could increase the expression of Ac-H3 and increase the expression of Ac-tubulin,suggesting that compound a6 may be a selective inhibitor of HDAC6;（4）compounds a6,a9 arrest cell cycle and induce apoptosis.The results showed that compounds a6 and a9 caused significant arrest in Hela cells in G0/G1phase and induced early apoptosis of HeLa cells.In summary,the study of this paper found a class of compounds that have good inhibitory activity against cervical cancer cells,and also enriched the library of HDAC inhibitor compounds.Compounds a6 and a9 are promising compounds that are potential HDAC inhibitors and can be used to treat cervical cancer.These compounds have in-depth research value.