Design and optimization of novel Tetrahydro-β-carboline-based HDAC inhibitors with potent activities against tumor cell growth and metastasis

[Display omitted] •A series of Tetrahydro-β-carboline-based hydroxamate derivatives as HDAC inhibitors were designed and synthesized.•Compound 11g showed potent HDAC1 inhibition.•Compound 11g effectively inhibited colony formation of A549 cells.•Compound 11g significantly inhibited the proliferation and promoted cycle arrest as well as apoptosis of A549 cells.•Compound 11g enhanced ROS generation and DNA damage accumulation to induce apoptosis in A549 cells. Histone deacetylases (HDACs) are validated drug targets for various therapeutic applications. A series of Tetrahydro-β-carboline-based hydroxamate derivatives, designed as HDAC inhibitors (HDACis), were synthesized. Compound 11g exhibited strong inhibitory activity against HDAC1 and the A549 cancer cell line. Additionally, this compound increased the levels of acetylated histone H3 and H4. Notably, 11g effectively arrested A549 cells in the G2/M phase and also increased ROS production and DNA damage, thereby inducing apoptosis. Further molecular docking experiments illustrated the potential interactions between compound 11g and HDAC1. These findings suggested that the novel Tetrahydro-β-carboline-based HDACis could serve as a promising framework for further optimization as anticancer agents.