A novel series of l-2-benzyloxycarbonylamino-8-(2-pyridyl)-disulfidyloctanoic acid derivatives as histone deacetylase inhibitors: Design, synthesis and molecular modeling study

Histone deacetylases inhibitors (HDACIs) have become an attractive class of anticancer agents. In order to find some novel potent HDACIs, we designed and synthesized a series of l-2-benzyloxycarbonylamino-8-(2-pyridyl)-disulfidyloctanoic acid derivatives. All compounds exhibited potent HDAC-inhibitory activity, and two of them had similar potency to TSA. The introduction of 2-amino-4-phenylthiazole or 9-methyleneoxy-fluorenyl group at the surface recognize domain of these HDACIs could greatly increase their HDAC-inhibitory activity. Molecular modeling studies indicated that coordination of the zinc ion by these inhibitors, and formation of hydrogen bond and hydrophobic interaction between inhibitors and HDACs were essential for the HDAC-inhibitory activities of these inhibitors. Asp181, Asp269, Leu276 and Tyr308 in the active site of HDAC2 gave favorable contributions for binding with all compounds.

Graphical AbstractA series of l-2-benzyloxycarbonylamino-8-(2-pyridyl)-disulfidyloctanoic acid derivatives were designed and synthesized as novel potent HDACIs, and the interactions between all compounds and HDAC2 were investigated by molecular modeling study.Figure optionsDownload as PowerPoint slideHighlights
► A series of novel potent histone deacetylase (HDAC) inhibitors were synthesized.
► The HDAC-inhibitory abilities of two compounds were at the same level as TSA.
► The interactions between these compounds and HDAC2 were explored.