title: Discovery of pyridone-based histone deacetylase inhibitors: approaches for metabolic stability.
abstract: Histone deacetylases (HDACs) are important enzymes in epigenetic regulation and are therapeutic targets for cancer. Most zinc-dependent HDACs induce proliferation, dedifferentiation, and anti-apoptotic effects in cancer cells. We designed and synthesized a new series of pyridone-based HDAC inhibitors that have a pyridone ring in the core structure and a conjugated system with an olefin connecting the hydroxamic acid moiety. Consequently, most of the selected pyridone-based HDAC inhibitors showed similar or higher inhibition profiles in addition to remarkable metabolic stability against hydrolysis relative to the corresponding lactam-based HDAC inhibitors. Furthermore, the selectivity of the novel pyridine-based compounds was evaluated across all of the HDAC isoforms. One of these compounds, (E)-N-hydroxy-3-{1-[3-(naphthalen-2-yl)propyl]-2-oxo-1,2-dihydropyridin-3-yl}acrylamide, exhibited the highest level of HDAC inhibition (IC(50) =0.07 μM), highly selective inhibition of class I HDAC1 and class II HDAC6 enzymes, metabolic stability in mouse liver microsomal studies, and effective growth inhibition of various cancer cell lines. Docking studies indicated that a long alkyl linker and bulky hydrophobic cap groups affect in vitro activities. Overall, the findings reported herein regarding pyridone-based HDAC inhibitors can be used to guide future research efforts to develop new and effective anticancer therapeutics.
authors.affiliation: Translational Research Center for Protein Function Control (TRCP), Department of Biotechnology and Department of Biomedical Sciences (WCU Program), Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Misun
authors.initials: M
authors.lastname: Cho
authors.forename: Eunhyun
authors.initials: E
authors.lastname: Choi
authors.forename: Jee Sun
authors.initials: JS
authors.lastname: Yang
authors.forename: Chulho
authors.initials: C
authors.lastname: Lee
authors.forename: Jeong Jea
authors.initials: JJ
authors.lastname: Seo
authors.forename: Beom Seok
authors.initials: BS
authors.lastname: Kim
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D011728:Pyridones; D006655:Histone Deacetylases