Synthesis,Biological Evaluation and Molecular Modeling of Cyclic Tetrapeptide Based Inhibitors HDAC

Histone deacetylases（HDACs） are considered to be among the most promising targets for the development of anti-cancer drugs,and HDAC inhibitors（HDACIs） have become a promising class of anti-cancer drugs.To explore whether thioacetyl group as the zinc binding group（ZBG） and a slight change in the hydrophobicity of the recognition domain of HDACIs could alter their activities,we synthesized a series of cyclo[-L-Am7（SAc）-Aib-L-Phe（n-Cl）D-Pro-] and evaluated their HDAC-inhibitory and antiproliferative activities.The results show that these peptides could inhibit HDAC at 10-9 mol/L level,and could selectively inhibit the proliferation of three human cancer cell lines with IC 50 at 10-6 mol/L level.Docking study was conducted to examine the mechanisms by which these peptides interact with HDAC2.It appeared that a zinc ion in the active site of HDAC was coordinated by the carbonyl oxygen atom of the ZBG in the inhibitor.Both the ZBG domain of all the peptides and the surface recognition domain of cyclo[-L-Am7（SAc）-Aib-L-Phe（o-Cl）-D-Pro-] and that of cyclo[-L-Am7（SAc）-Aib-L-Phe（m-Cl）-D-Pro-] interacted with HDAC2 via hydrogen bonding.Hydrophobic interaction has been considered to provide favorable contributions to stabilizing the complexes,and the introduction of a chlorine atom at the aromatic ring on the L-Phe position of these peptides affected the interaction between each of these inhibitors and the enzyme,resulting in slight change in the structure of the surface recognition domain of the peptides.