title: Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors.
abstract: Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038μM; HDAC2, 0.0082μM; HDAC3, 0.015μM; HDAC8, 0.0060μM; HDAC4, 0.058μM; HDAC9, 0.0052μM; HDAC6, 0.058μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process.
authors.affiliation: Nippon Pharmaceutical Chemicals Co., Ltd, 2-8-18 Chodo, Higashi-Osaka, Osaka 577-0056, Japan. Electronic address: t-tashima@nichiri.co.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Tashima
authors.affiliation: Nippon Pharmaceutical Chemicals Co., Ltd, 2-8-18 Chodo, Higashi-Osaka, Osaka 577-0056, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Murata
authors.affiliation: Nippon Pharmaceutical Chemicals Co., Ltd, 2-8-18 Chodo, Higashi-Osaka, Osaka 577-0056, Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Kodama
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D006655:Histone Deacetylases
keywords: Cancer; Carbostyril; Epigenetics; Histone deacetylase; Histone deacetylase inhibitor