Design, Synthesis And Structure-activity Relationship Study Of Novel Histone Deacetylase Inhibitors

Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression by catalyzing the removal of acetyl groups from lysine residues clustered near the amino terminus of nucleosomal histones, and thus stimulating chromatin condensation and promoting transcriptional repression. HDAC inhibitors can induce cell cycle arrest, promote differentiation and stimulate tumor cell death. HDACs have been proved as promising targets for anticancer drug discovery.Based on the analysis of the SAHA binding site in Histone deacetylase-like protein (HDLP), a HDAC homologue, shares 35.2% identity with human HDAC1 over 375 residues, it was found that there exists an empty hydrophobic area formed by PHE₁41, PHE₁98, PHE₂00, GLU₉2 and TYR₉1. Additional interactions of any ligand to it might be helpful to increase the binding affinity. Thus, two series of target compounds were precisely designed based on diverse docking methods.Appropriate starting materials were used and target compounds were synthesized by multiple steps. All structures of target compounds were confirmed by 1H NMR, LC/MS, HRMS, IR and HPLC analysis.All target compounds were screened against pan-HADCs for enzymatic inhibitory activities. Among them,44 was most potent compound with 78.70% inhibition in 2μM.Structure-activity relationship (QSAR) study was also carried based on the testing compounds from the present report. The QSAR model confirmed the above potential hydrophobic pocket.However, more well-designed compounds are still needed to be synthesized and screened in order to demonstrate the function of the above hypothesis.In summary, two series of compounds targeting to the potential hydrophobic pocket was synthesized and all compounds demonstrated pan-HDAC inhibitory activities as predicted.