Design,Synthesis And Antitumor Effects Of HDAC Inhibitors Based On The Trans-aryl Allyl Acyl Tetrahydroisoquinoline Nucleus

Histone deacetylase inhibitors（HDACIs）are a kind of cancer treatment drugs with great research value.With the aim to explore novel high-efficiency HDACIs,in this thesis we designed and synthesized a series of HDACIs with trans-aryl allyl tetrahydroisoquinoline parent nuclei,and evaluated its anti-tumor activity in vitro.The results of HDAC1 inhibitory enzyme activity test validated that 8e,8f and 9e had better inhibitory activity than the markted drug SAHA,of which 8e had the strongest inhibitory activity,with an IC₅₀value of 3.8 n M.The tumor cell proliferation inhibitory activity results confirmed that 9f had the strongest antiproliferative effects on both A549 and HCT116 tumor cells,with GI₅₀ values of 0.89±0.07μM and 0.49±0.03μM,respectively,which were battering the marketed drugs SAHA.The inhibitory activity of some compounds on HDAC6 certified that 8e,9e,21 had superior inhibitory activities than SAHA,and 8e had the highest inhibitory activity on HDAC6 with IC₅₀ of 7.4 n M.21 inhibits HDAC6 nearly 30 times higher activity than HDAC1.23 had very weak inhibitory activity on HDAC1,and demonstrated a certain inhibitory activity on HDAC6.21 and 23 exhibited some subtype selectivity for HDAC inhibition.The effect of 8e on the expression of histone H3 andα-tubulin acetylation level was firmed by Western blot.The results displayed that 8e could significantly promote the acetylation level of histone H3 andα-tubulin in a dose-dependent manner.Molecular simulation docking experiments reveal that the surface recognition groups of 8e and 21 can interact well with the hydrophobin surfaces of HDAC1/6 and HDAC6,respectively.The 8e six-carbon long fatty chain connecting arm can better enter the HDAC1/6 catalytic channel,which is beneficial for the hydroxamic acid group in the structure to form hydrogen bonds with the amino acid residues at the bottom of the active pocket,and can chelate or coordinate with Zn²⁺.The benzene ring connecting arm of 21 has poor matching with the HDAC1 catalytic channel,but can enter the short and wide catalytic channel of HDAC6,which is conducive to the function of the hydroxamic acid group in the structure.The above results laid the foundation for further optimization and development of competent and selective HDACIs.