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.
Result: 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.Keywords: Histone Deacetylase Inhibitors, Benzodiazepine, Natural peptides, Peptidomimetics, Stereoselective synthesis, Antiproliferation.
Current Topics in Medicinal Chemistry
Title:Benzodiazepine Scaffold as Drug-like Molecular Simplification of FR235222: A Chemical Tool for Exploring HDAC Inhibition
Volume: 17 Issue: 4
Author(s): Rosario Randino, Ilaria Moronese, Elena Cini, Valentina Bizzarro, Marco Persico, Manuela Grimaldi, Mario Scrima, Anna Maria D`Ursi, Ettore Novellino, Eduardo Sobarzo-Sánchez, Luca Rastrelli, Caterina Fattorusso, Antonello Petrella, Manuela Rodriquez*Maurizio Taddei
Affiliation:
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, Fisciano (SA),Italy
Keywords: Histone Deacetylase Inhibitors, Benzodiazepine, Natural peptides, Peptidomimetics, Stereoselective synthesis, Antiproliferation.
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.
Result: 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.Export Options
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Cite this article as:
Randino Rosario, Moronese Ilaria, Cini Elena, Bizzarro Valentina , Persico Marco, Grimaldi Manuela, Scrima Mario, D`Ursi Maria Anna , Novellino Ettore, Sobarzo-Sánchez Eduardo, Rastrelli Luca, Fattorusso Caterina, Petrella Antonello, Rodriquez Manuela*, Taddei Maurizio, Benzodiazepine Scaffold as Drug-like Molecular Simplification of FR235222: A Chemical Tool for Exploring HDAC Inhibition, Current Topics in Medicinal Chemistry 2017; 17 (4) . https://dx.doi.org/10.2174/1568026616666160824105645
DOI https://dx.doi.org/10.2174/1568026616666160824105645 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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