Benzodiazepine Scaffold as Drug-like Molecular Simplification of FR235222: A Chemical Tool for Exploring HDAC Inhibition

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

Journal Name: Current Topics in Medicinal Chemistry

Volume 17 , Issue 4 , 2017

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Graphical 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.

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Article Details

Year: 2017
Page: [441 - 459]
Pages: 19
DOI: 10.2174/1568026616666160824105645
Price: $65

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