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Design and synthesis of novel hybrid benzamide-peptide histone deacetylase inhibitors.

ABSTRACT: 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.

SUBMITTER: Hu F

PROVIDER: S-EPMC3045849 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Design and synthesis of novel hybrid benzamide-peptide histone deacetylase inhibitors.

Hu Fang F Chou C James CJ Gottesfeld Joel M JM

Bioorganic & medicinal chemistry letters 20090325 14

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 ...[more]

PMID: 19362838

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