Design, Synthesis And Biological Evaluation Of Novel Cinnamic Hydroxamic Acid As HDAC Inhibitors

As continuous efforts in the anticancer drug discovery in the epigenetic field, chemical modification and optimization of lead compounds obtained in previously studies in our lab were carried out in order to improve the HDAC inhibitory activities.The homology model of HDAC1was built based on HDLP. The target compounds were designed according to analysis of the amino acid residues around the binding pocket of HDAC1. All important key intermediates and/or part of target compounds were synthesized either by the procedures from our lab. The enzymatic inhibition was measured according to the protocol reported.22target compounds were synthesized and characterized by1H-NMR, MS or HRMS. The enzyme assay revealed that7compounds showed enzymatic inhibitory activities against the pan-HDAC above65%at the concentratin of2μM. Compound30exhibited comparable inhibitory activities to that of SAHA at the same concentration.All tested compounds showed moderate to good pan-HDAC enzyme inhibitory activities. Compounds with electron-rich aromatic group sidechains show better inhibitory activities. A proper aliphatic sidechain with polar tail might increase the HDAC inhibitory activities of the target compounds. The amino acid residues at entrance of the binding pocket played a very important role in the initial recognition of compound.