title: Histone deacetylase inhibitors through click chemistry.
abstract: Histone deacetylase inhibitors (HDACi) are a relatively new class of chemotherapy agents. Herein, we report a click-chemistry based approach to the synthesis of HDACi. Fourteen agents were synthesized from the combination of two alkyne and seven azido precursors. The inhibition of HDAC1 and HDAC8 was then determined by in vitro enzymatic assays, after which the cytotoxicity was evaluated in the NCI human cancer cell line screen. A lead compound 5 g (NSC746457) was discovered that inhibited HDAC1 at an IC(50) value of 104 +/- 30 nM and proved quite potent in the cancer cell line screen with GI(50) values ranging from 3.92 microM to 10 nM. Thus, this click HDACi design has provided a new chemical scaffold that has not only revealed a lead compound, but one which is easily amendable to further structural modifications given the modular nature of this approach.
authors.affiliation: Department of Biochemistry, The Ohio State University, 876 Biological Sciences Building, 484 West 12th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Robert
authors.initials: R
authors.lastname: Woodward
authors.forename: James Patrick
authors.initials: JP
authors.lastname: Kedenburg
authors.forename: Xianwei
authors.initials: X
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Lanyan
authors.initials: L
authors.lastname: Fang
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001386:Azides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013237:Stereoisomerism; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C539552:3-(1-cinnamyl-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide; D000480:Alkynes; D001386:Azides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014230:Triazoles