Design,Synthesis And Antitumor Activity Evaluation Of 2-amino-N-(6-oxo-6-(Phenylamino)Hexyl) Benza Mides As HDACIs

The histone acetylation and deacetylation is closely related to the development of tumor,and with the deepening of HDAC research,it has become one of the hot targets of anti-tumor drug discovery.Among the HDACIs,the hydroxamic acid compounds are the most representative,but the stability of the ZBG of the hydroxamic acid compounds is poor in vivo and the ZBG is easily metabolized.In this paper,a class of HDAC inhibitors with novel Zn2+ binding groups were designed and synthesized.We expected that the new compounds had better activity and better stability.We also carried out all kinds of evaluations for the new compounds,including a series of biological activity tests and computer simulation experiments.(1)The compounds with novel Zn2+ chelating groups(o-aminobenzamide)were synthesized by the o-nitrobenzoic acid,6-aminocaproic acid and substituted aniline.The chemistry structures of 13 compounds were confirmed by 1H-NMR and EI-MS.(2)Tumor cell inhibition experiments revealed that the Compound E3(IC50= 1.91μM)possessed a higher activity against Hep-G2,better than the activity of the positive control SAHA(IC50=1.95μM).The analysis of structure-activity relationship showed that the compounds′ benzene ring 3-substituted> 4-substituted and the activity was better when it was replaced by-CF3,-F or –Cl groups.The dose-effect relationship of the E3 has shown that there is a certain concentration-dependent on tumor cells.(3)The cell cycle and apoptosis revealed that compound E3 not only has a certain induction of apoptosis,and block cells G0 / G1 phase effect is strong,suggesting that E3 could reach the anti-tumor proliferation by inducing apoptosis and blocking the G0/G1 phase effect.(4)The molecular docking studies and kinetic simulation showed that E3 can be stably docked to the HDAC active chamber by hydrophobic interaction,hydrogen bonding and electrostatic interaction.What’s more,this is highly consistent with the SAHA docking structure.