Discovery Of Hdacis With Novel Zn²⁺ Binding Group:Design,Synthesis And Activity Evaluation Of N-?6-??2-Hydroxyethyl?Amino?-6-oxohexyl? Benzamides

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.These histone deacetylase inhibitors(HDACIs),which possess a three distinct domains(CAP,LINKER,ZBG),have achieved good results in clinical practice.Among them,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.What's worse,it is very toxic to normal cells.In this paper,one 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(hydroxyethylamino acyl)were synthesized by the substituted benzoic acid,6-aminocaproic acid,ethanolamine and its derivatives.The chemistry structures of 15 compounds were confirmed by 1H-NMR,13C-NMR and EI-MS;(2)Tumor cell inhibition experiments revealed that the compounds were more sensitive to A549(IC50=1.68~32.32?M),particularly with activity of compound e8(IC50=1.68?M),showing better activity than the positive control SAHA(IC50=4.85 ?M).The analysis of structure-activity relationship showed that when the compounds? cap group volume is big the activity is better than others and the hydroxyethylamino group(ZBG)is a reactive group.The dose-effect relationship of the e8 has shown that there is a certain concentration-dependent on three tumor cells;(3)The cell cycle and apoptosis revealed that compound e8 has a strong effect on the cell G0/G1 phase arrest,and has a certain ability to induce apoptosis of tumor cells,suggesting that compound e8 may play a role in inhibiting tumor cell proliferation by a strong role in arresting cell cycle and a certain induced apoptosis;(4)The molecular docking studies and molecular dynamic simulation showed that the compound e8 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 and TSA docking structure.Therefore,compound e8 is of further research value and is expected to develop into a new HDAC inhibitor.