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 IC(50) values ranging from 1.3 microM to 532 microM. Interestingly, compound 15 showed 19-fold selectivity for HDAC3 versus HDAC1.
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Fang
F
Hu
C James
CJ
Chou
Joel M
JM
Gottesfeld
D001549:Benzamides / Q000737:chemistry*; D003500:Cyclization; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D000099186:Histone Deacetylase 3
D001549:Benzamides; D004791:Enzyme Inhibitors; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D018696:Neuroprotective Agents; D010455:Peptides; D000099186:Histone Deacetylase 3; C037689:benzamide; C110550:HDAC1 protein, human