Design, Synthesis, and Antitumor Activities of Novel Coumarin-Based Histone Deacetylase Inhibitors.

Histone deacetylases (HDACs) are important epigenetic regulatory enzymes contributing to cancer proliferation, which could be critical targets in cancer therapy. The structural similarities of the existing HDAC inhibitors have resulted in an increase in the drug resistance. In this study, coumarin was employed as the core scaffold for structural derivatisation to develop a novel class of HDAC inhibitors based on computer-aided design (CADD). Their anti-tumor activity was evaluated against esophageal squamous cell lines. The results showed that most compounds exhibited potent anti-proliferative activity against KYSE70 and KYSE150. Among them, compound 4s and 4p exhibited the most potent activity with IC50 values of 3.44 μM and 3.39 μM against KYSE70. To validate the target of the synthesized compounds, transcriptome sequencing was performed and the results revealed that a total of 487 genes were differentially expressed, including 190 up-regulated and 297 down-regulated genes. Among these, 79 genes were associated with the HDAC regulatory network, accounting for 16.2% of the differentially expressed genes. Molecular docking demonstrated that compound 4s could effectively enter the active site of HDAC, engaging with the cap group, zinc-binding group, and linker region. This multiple interaction network provides a structural basis for the potent inhibitory activity of compound 4s. In conclusion, a series of novel HDAC inhibitors with a coumarin scaffold were discovered, and their mode of action was revealed. This provides a valuable guide for the development of novel HDAC-targeting therapeutics.