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.

本研究报道了一类以类肽衍生帽基为结构单元、搭载不同锌结合基团的聚焦型组蛋白去乙酰化酶（histone deacetylase, HDAC）抑制剂库的多组分合成方法。所合成的全部化合物均通过细胞HDAC抑制活性检测与MTT细胞毒性检测开展活性评价。基于其在细胞HDAC抑制实验中展现出的优异活性，我们进一步筛选出4种化合物，测试其对重组HDAC1-3、HDAC6及HDAC8的抑制活性。结果表明，这4种化合物均对HDAC1-3表现出强效抑制作用，同时对HDAC6也具有显著抑制活性，半数抑制浓度（IC50）处于亚微摩尔浓度区间。其中，化合物4j是细胞HDAC抑制实验中活性最强的抑制剂，展现出突出的化学增敏特性，可将顺铂耐药头颈癌细胞系Cal27CisR对顺铂的敏感性提升近7倍。此外，4j几乎完全逆转了Cal27CisR的顺铂耐药性，该效应与4j联合顺铂时所产生的协同诱导细胞凋亡作用密切相关。