title: Benzodiazepine Scaffold as Drug-like Molecular Simplification of FR235222: A Chemical Tool for Exploring HDAC Inhibition.
abstract: BACKGROUND
  Synthesis, computational study and biological evaluation of peptidomimetic analogues of FR235222 (3), a natural immunosuppressant and HDAC inhibitor, have been reported. These new compounds, bearing α-hydroxyketone moiety, as more stable zinc binding group (ZBG), were evaluated in vitro as HDAC inhibitors against the human HDACs isoforms 1-9 and in cellular antiproliferative assays on U937 human leukemia cell line. The 1,4-benzodiazepin-2,5-dione (BDZ), capping group and the natural ZBG, (S,R)-2-amino-9-hydroxy-8-oxodecanoic acid (Ahoda), were evaluated in order to probe HDAC inhibition and/or paralogue selectivity. Some of the new derivatives showed an interesting activity against a number of HDAC isozymes. The observed activity profile was rationalized by a computational assisted SAR study, in order to understand how the BDZ classes interact with the enzyme into the catalytic pocket. Despite its poor solubility, compound 17b showed significant antiproliferative profile and HDAC inhibition activity.
  
  
  RESULTS
  In order to assess how the solubility issue could have affected the biological outcome, bioassay conditions were reproduced and quantification of precipitated particulate material was evaluated by turbidimetric and NMR studies together with physicochemical descriptors prediction. Thus, BDZ 17b has been chosen to be promising lead compounds for further optimization, in order to elucidate molecule- enzyme surface recognition.
authors: Rosario
authors: R
authors: Randino
authors: Ilaria
authors: I
authors: Moronese
authors: Elena
authors: E
authors: Cini
authors: Valentina
authors: V
authors: Bizzarro
authors: Marco
authors: M
authors: Persico
authors: Manuela
authors: M
authors: Grimaldi
authors: Mario
authors: M
authors: Scrima
authors: Anna Maria
authors: AM
authors: D'Ursi
authors: Ettore
authors: E
authors: Novellino
authors: Eduardo
authors: E
authors: Sobarzo-Sanchez
authors: Luca
authors: L
authors: Rastrelli
authors: Caterina
authors: C
authors: Fattorusso
authors: Antonello
authors: A
authors: Petrella
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, Fisciano (SA), Italy.
authors: Manuela
authors: M
authors: Rodriquez
authors: Maurizio
authors: M
authors: Taddei
mesh_terms: D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C474179:FR 235222; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D001569:Benzodiazepines