Design and synthesis of novel hybrid benzamide–peptide histone deacetylase inhibitors

We designed and synthesized a series of novel hybrid histone deacetylase inhibitors based on conjugation of benzamide-type inhibitors with either linear or cyclic peptides. Linear tetrapeptides (compounds 13 and 14), cyclic tetrapeptides (compounds 1 and 11), and heptanediamide–peptide conjugates (compounds 10, 12, 15 and 16) were synthesized through on-resin solid-phase peptide synthesis (SPPS). All compounds were found to be moderate HDAC1 and HDAC3 inhibitors, with IC50 values ranging from 1.3 μM to 532 μM. Interestingly, compound 15 showed 19-fold selectivity for HDAC3 versus HDAC1.

Novel hybrid benzamide–peptide histone deacetylase inhibitors have been synthesized and structural–activity relationships are detailed, along with enzyme and cellular activities.Figure optionsDownload as PowerPoint slide