Design and synthesis of novel histone deacetylase inhibitor derived from nuclear localization signal peptide.
We describe herein the synthesis and characterization of a new class of histone deacetylase (HDAC) inhibitors derived from conjugation of a suberoylanilide hydroxamic acid-like aliphatic-hydroxamate pharmacophore to a nuclear localization signal peptide. We found that these conjugates inhibited the histone deacetylase activities of HDACs 1, 2, 6, and 8 in a manner similar to suberoylanilide hydroxamic acid (SAHA). Notably, compound 7b showed a threefold improvement in HDAC 1/2 inhibition, a threefold increase in HDAC 6 selectivity and a twofold increase in HDAC 8 selectivity when compared to SAHA.
School of Chemistry and Biochemistry, Parker H Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
Joshua C
JC
Canzoneri
Po C
PC
Chen
Adegboyega K
AK
Oyelere
D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000737:chemistry; D008968:Molecular Conformation; D019913:Nuclear Localization Signals / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019913:Nuclear Localization Signals; D006655:Histone Deacetylases