Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups

In this work, we report the multicomponent
synthesis of a focused
histone deacetylase (HDAC) inhibitor library with peptoid-based cap
groups and different zinc-binding groups. All synthesized compounds
were tested in a cellular HDAC inhibition assay and an MTT assay for
cytotoxicity. On the basis of their noteworthy activity in the cellular
HDAC assays, four compounds were further screened for their inhibitory
activity against recombinant HDAC1–3, HDAC6, and HDAC8. All
four compounds showed potent inhibition of HDAC1–3 as well
as significant inhibition of HDAC6 with IC50 values in
the submicromolar concentration range. Compound 4j, the
most potent HDAC inhibitor in the cellular HDAC assay, revealed remarkable
chemosensitizing properties and enhanced the cisplatin sensitivity
of the cisplatin-resistant head–neck cancer cell line Cal27CisR
by almost 7-fold. Furthermore, 4j almost completely reversed
the cisplatin resistance in Cal27CisR. This effect is related to a
synergistic induction of apoptosis as seen in the combination of 4j with cisplatin.