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<p>Histone deacetylases (HDACs) are established as valuable drug targets for cancer therapy. A set of hydroxamate derivatives based on tetrahydro-γ-carboline were specifically designed and synthesized as HDAC inhibitors. Among these, 8-(8-bromo-5-isobutyl-1,3,4,5-tetrahydro-2<i>H</i>-pyrido[4,3-<i>b</i>]indol-2-yl)-<i>N</i>-hydroxy-8-oxooctanamide demonstrated potent inhibitory effects on HDAC1 and A549 cancer cell lines. Moreover, this compound was found to increase the levels of acetylated histone H3 and H4. Notably, it effectively arrested A549 cells in the G2/M phase, while also enhancing ROS production and accumulating DNA damage to induce apoptosis. Molecular docking provided insights into the potential interaction between this compound and HDAC1. These results suggested that these novel HDAC inhibitors based on tetrahydro-γ-carboline could represent a promising foundation for further optimization as potential anticancer agents.</p> Graphical abstract <p></p>

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Development of tetrahydro-γ-carboline-based histone deacetylase inhibitors with antitumor activities

  • 期刊论文

  • 发表日期：

    2025年6月19日

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  • Zeyi Wan,
  • Xiangzhi Li,
  • Yuhua Qu,
  • Shule Fan,
  • Wenxia Lu,
  • Linlin Xu,
  • Feifei Yang,
  • Hua Zhang

摘要

Histone deacetylases (HDACs) are established as valuable drug targets for cancer therapy. A set of hydroxamate derivatives based on tetrahydro-γ-carboline were specifically designed and synthesized as HDAC inhibitors. Among these, 8-(8-bromo-5-isobutyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-N-hydroxy-8-oxooctanamide demonstrated potent inhibitory effects on HDAC1 and A549 cancer cell lines. Moreover, this compound was found to increase the levels of acetylated histone H3 and H4. Notably, it effectively arrested A549 cells in the G2/M phase, while also enhancing ROS production and accumulating DNA damage to induce apoptosis. Molecular docking provided insights into the potential interaction between this compound and HDAC1. These results suggested that these novel HDAC inhibitors based on tetrahydro-γ-carboline could represent a promising foundation for further optimization as potential anticancer agents.

Graphical abstract