title: Design and synthesis of phenolic hydrazide hydrazones as potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors.
abstract: Poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) are enzymes responsible for catalyzing the formation and degradation of poly(ADP-ribose) (PAR) polymers, respectively. Activation of PARP has been shown to be involved in cell death induced by genotoxic stimuli. On the other hand, genetic disruption of PARG also leads to increased level of cell death by accumulation of PAR. Unlike PARP, where significant medicinal effort has been expended to identify potent inhibitors, PARG has been insufficiently investigated as a molecular therapeutic target. In this study, we report the design, synthesis, and biological evaluation of phenolic hydrazide hydrazones as potent PARG inhibitors. Compounds 3d, 3e, 5d, 5e, 8a, 8b and 8c showed their ability to inhibit the catalytic activity of PARG in vitro with IC50 values of 1.0, 2.1, 3.1, 3.2, 3.1, 2.8 and 1.6 μM, respectively.
authors.affiliation: Department of Medical Technology, Kumamoto Health Science University, 325 Izumi-machi, Kumamoto 861-5598, Japan.
authors.forename: Rafiqul
authors.initials: R
authors.lastname: Islam
authors.affiliation: Sien-Lab, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Koizumi
authors.affiliation: Sien-Lab, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kodera
authors.affiliation: Pharma Valley Center, 1007 Shimonagakubo, Nagaizumi-machi, Shuntougn, Shizuoka Prefecture 411-4777, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Medical Technology, Kumamoto Health Science University, 325 Izumi-machi, Kumamoto 861-5598, Japan. Electronic address: okawara@kumamoto-hsu.ac.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okawara
authors.affiliation: Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D010636:Phenols / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006835:Hydrazones; D010636:Phenols; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase
keywords: Hydrazide-hydrazone; Inhibitor; Molecular docking; PARG; PARP; Synthesis