title: Synthesis of a selective HDAC6 inhibitor active in neuroblasts.
abstract: In recent years, the role of HDAC6 in neurodegeneration has been partially elucidated, which led some authors to propose HDAC6 inhibitors as a therapeutic strategy to treat neurodegenerative diseases. In an effort to develop a selective HDAC6 inhibitor which can cross the blood brain barrier (BBB), a modified hydroxamate derivative (compound 3) was designed and synthetized. This compound was predicted to have potential for BBB penetration based on in silico and in vitro evaluation of passive permeability. When tested for its HDAC inhibitory activity, the IC50value of compound 3 towards HDAC6 was in the nM range in both enzymatic and cell-based assays. Compound 3 showed a cell-based selectivity profile close to that of tubastatin A in SH-SY5Y human neuroblastoma cells, and a good BBB permeability profile.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zwick
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Simões-Pires
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland; Département de Biochimie, Université de Montréal, H3C 3J7 Montréal, Québec, Canada.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Petit
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
authors.forename: Carolina
authors.initials: C
authors.lastname: Dos Santos Passos
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
authors.forename: Giuseppe Marco
authors.initials: GM
authors.lastname: Randazzo
authors.affiliation: Institut de chimie, UMR CNRS 7272, UNSA, F-06108 Nice, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Martinet
authors.affiliation: Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 521106, B28, 86073 Poitiers, France; Réseau Epigénétique du Cancéropôle Grand Ouest, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland. Electronic address: muriel.cuendet@unige.ch.
authors.forename: Muriel
authors.initials: M
authors.lastname: Cuendet
mesh_terms: D001812:Blood-Brain Barrier; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D009474:Neurons / Q000187:drug effects*
chemical_list: D056572:Histone Deacetylase Inhibitors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; Histone deacetylases; Isoform selectivity; Neuroblastoma cells; PAMPA