Background:
Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer
agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides
have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural
classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and
belinostat (PXD-101).
Aims:
This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides
scaffolds with potential cytotoxicity against different cancer cell lines.
Methods:
Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed
based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for
HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal
adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer).
Molecular simulations were finally carried out to gain more insight into the structure-activity relationships.
Results:
It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency
and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than
suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited
HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds
bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher
binding affinities.
Conclusions:
The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized
were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be
warranted.
A Multiple-Loop, Double-Cube Microarray Design Applied to Prostate Cancer Cell Lines with Variable Sensitivity to Histone Deacetylase Inhibitors
