title: Histone deacetylase (HDAC) inhibitors with a novel connecting unit linker region reveal a selectivity profile for HDAC4 and HDAC5 with improved activity against chemoresistant cancer cells.
abstract: The synthesis and biological evaluation of new potent hydroxamate-based HDAC inhibitors with a novel alkoxyamide connecting unit linker region are described. Biological evaluation includes MTT and cellular HDAC assays on sensitive and chemoresistant cancer cell lines as well as HDAC profiling of selected compounds. Compound 19i (LMK235) (N-((6-(hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide) showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. Subsequent HDAC profiling yielded a novel HDAC isoform selectivity profile of 19i in comparison to vorinostat or trichostatin A (TSA). 19i shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie,  Heinrich Heine Universität , Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Marek
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hamacher
authors.forename: Finn K
authors.initials: FK
authors.lastname: Hansen
authors.forename: Krystina
authors.initials: K
authors.lastname: Kuna
authors.forename: Holger
authors.initials: H
authors.lastname: Gohlke
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Thomas
authors.initials: T
authors.lastname: Kurz
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D012097:Repressor Proteins / Q000187:drug effects*; D013055:Spectrophotometry, Infrared
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; D006655:Histone Deacetylases