title: Synthesis and SAR assessment of novel Tubathian analogs in the pursuit of potent and selective HDAC6 inhibitors.
abstract: The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emerging field in medicinal chemistry. In this paper, the preparation and assessment of thirteen selective HDAC6 inhibitors is disclosed, elaborating on a previously developed thiaheterocyclic Tubathian series. All compounds were evaluated in vitro for their ability to inhibit HDAC6, and a selection of five potent compounds was further screened toward all HDAC isoforms (HDAC1-11). The capability of these Tubathian analogs to inhibit α-tubulin deacetylation was assessed as well, and ADME/Tox data were collected. This thorough SAR evaluation revealed that the oxidized, para-substituted hydroxamic acids can be recognized as valuable lead structures in the pursuit of novel potent and selective HDAC6 inhibitors.
authors.affiliation: SynBioC Research Group, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. matthias.dhooghe@UGent.be.
authors.forename: Rob
authors.initials: R
authors.lastname: De Vreese
authors.affiliation: SynBioC Research Group, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. matthias.dhooghe@UGent.be.
authors.forename: Yves
authors.initials: Y
authors.lastname: Depetter
authors.affiliation: Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Verhaeghe
authors.affiliation: Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Desmet
authors.affiliation: Laboratory of Neurobiology and Vesalius Research Center (VIB), Research Institute for Neuroscience and Disease (LIND), KU Leuven, Belgium.
authors.forename: Veronick
authors.initials: V
authors.lastname: Benoy
authors.affiliation: Laboratory of Neurobiology and Vesalius Research Center (VIB), Research Institute for Neuroscience and Disease (LIND), KU Leuven, Belgium.
authors.forename: Wanda
authors.initials: W
authors.lastname: Haeck
authors.affiliation: Laboratory of Neurobiology and Vesalius Research Center (VIB), Research Institute for Neuroscience and Disease (LIND), KU Leuven, Belgium.
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.affiliation: SynBioC Research Group, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. matthias.dhooghe@UGent.be.
authors.forename: Matthias
authors.initials: M
authors.lastname: D'hooghe
mesh_terms: D004305:Dose-Response Relationship, Drug; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases