HDAC Inhibitiors: Design, Synthesis And Biological Evaluation Of Analoges Of LBH589

Object:To discover promising back-up compounds of NFY-270, which now have been in application for clinical trial, a series of novel HDAC inhibitors were designed, synthesized and evaluated in vitro.Research Methods:The most potent HDAC inhibitor LBH589 was selected as the lead compound, and the homology model of HDAC1 was built as the receptor. Based on molecular modeling studies of LBH589, a series of novel cinnamic hydroxamic acid HDAC inhibitors were designed, synthesized and bioassayed in vitro according to the paper.Results:A new synthetic route was reported, and eighteen novel cinnamic hydroxamic acid derivatives were synthesized. All related intermediates and target compounds were characterized by 1HNMR, 13CNMR, MS or HRMS. The bioassay results indicated that all target compounds showed moderate to potent pan-HDAC inhibitory activities. Among them, compound 3b-6,3c-3 and 3c-6 were found to inhibit HDACs with IC50 of 0.50μM,0.78μM and 0.36μM, respectively.Conclusions:1) The target compounds all showed potent pan-HDAC inhibitory activities; 2) The compounds of seriesⅡandⅢwere more active than seriesⅠ; 3) In comparison aliphatic group, aromatic group was a better substituent for R1; 4) The compound 3c-6, which was found to almost have the same anti-HDACs activity with NFY-270 (pan-HDAC IC50=0.22μM), may be a potential candidate of NFY-270; 5)This preliminary results may provide insight into the structural requirements for potent HDAC inhibitors.