Background:
Target-based approach to drug discovery currently attracts a great deal of interest from
medicinal chemists in anticancer drug discovery and development. Histone deacetylase (HDAC) inhibitors represent an
extensive class of targeted anti-cancer 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 vorinostat and
belinostat.
Aims:
This study aims at developing novel HDAC inhibitors bearing conjugated quinazolinone scaffolds with potential
cytotoxicity against different cancer cell lines.
Method:
A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin-4(3H)-
ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three
human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain
more insight into the structure-activity. relationships.
Results:
It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds
15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f
displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with
IC50 value of 1.86 µM, and HDAC inhibition with IC50 value of 6.36 µM. Docking experiments on HDAC2 isozyme
showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol
compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be
more cytotoxic toward SKLu-1than MCF-7 and HepG-2.
Conclusion:
The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the
results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.