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.