Design,Synthesis And Biological Evaluation Of Selective HDAC8 Inhibitors

Histone deacetylases(HDACs)are wide existed in human body and is related with removing acetyl group on the ε-amino group of the acetylated lysine of histones and performing epigenetic regulation.It becomes a drug target for various pathological conditions,such as cancer,metabolic and immune diseases,inflammation,viral and parasitic infections,neurodegenerative diseases,etc.At present,five drugs have been approved for cancer treatment,and a large number of new HDAC inhibitors are also in the clinical and preclinical research stage.However,the currently marketed HDAC inhibitors are all pan-inhibitors and lead to inevitable adverse reactions.Therefore,the research of subtype selective inhibitors has attracted more and more attention,especially in the field of developing anticancer agents.As a zinc ion-dependent enzyme,histone deacetylase 8(HDAC8)belongs to the HDAC class I subfamily and is widely distributed in the nucleus and cytoplasm.HDAC8 has many kind of substrates,such as histones,SMC3,estrogen-related receptor alpha(ERRα),p53 and ARID1a,etc.,so it can participate in various life activities,and i abnormal expression can cause cancers.In this paper,it is found that there is a "foot pocket" near the active site by analyzing the crystal structure of HDAC8 and PCI-34051,which can accommodate the hydrophobic group.Therefore,we use PCI-34051 as the lead compound to design series A compounds,replacing the hydroxamic acid group with different substituted hydrazides.Combining with the previous research on HDAC8 inhibitors based on the tetrahydroisoquinoline,target series B compounds were designed according to following strategies:(1)tetrahydroquinoline was used as the linking group;(2)hydrazide or hydroxamic acid group were used as ZBG;(3)benzyl group was used as the enzyme surface recognition group.In this thesis,twenty new intermediates were synthezied and totally forty-seven new compounds were obtained.Structures of all target compounds were identified.Preliminary biological evaluation were performed in vitro on HDAC8 enzyme inhibition on target compounds.Then target compounds with good inhibitory activities were tested their HDAC subtype selectivities,anti-proliferative activities and western blot experiments.The preliminary biological activity evaluation results show that the inhibitory activity of all compound against HDAC8 is significantly higher than that of the pan-HD AC inhibitor SAHA.In Western blotting experiments,the target compound Lw-3 can effectively increase the acetylation level of SMC3,but has little effect on the acetylation level of Tubulin and H3.In the HDAC subtype selective inhibition experiment,which confirmed its HDAC8 selectivities in celluar level.Target compounds Lw-18 and Lw-22 showed better anti-proliferative activities against six tumor cell lines compared with PCI-34051,which could be helpful in our further step on drug discovery.