Structure-based optimization of click-based histone deacetylase inhibitors

Previously, we reported a click-chemistry based approach to the synthesis of a novel class of histone deacetylase (HDAC) inhibitors [1]. The lead compound NSC746457 was found to be as potent as SAHA (Vorinostat). Further optimization of NSC746457 by using the HDAC2-TSA crystal structure is described herein. Docking of NSC746457 into HDAC2 binding domain suggested that the hydrophobic residue Phe210 flanking the cap-group binding-motif could be exploited for structural optimization. Substitution on the methylene group of cinnamic cap region led to identification of more potent HDAC inhibitors: isopropyl derivative 5 and tert-butyl derivative 6, with an IC50 value of 22 nM and 18 nM, respectively.

Graphical abstractOptimization of lead compound NSC746457 led to identification of two compounds with potent activity against HDAC enzymes.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The lead compound NSC746457 was optimized using the HDAC2-TSA crystal structure. ► Docking the NSC746457 into the histone deacetylase 2 suggested that Phe210 could be exploited for structure optimization. ► A series of novel HDAC inhibitors was designed and synthesized and two compounds showed strong activity against HDAC enzymes.