Design, Synthesis, and Structure-Activity relationships of Evodiamine-Based topoisomerase (Top)/Histone deacetylase (HDAC) dual inhibitors

Bioorg Chem. 2022 May:122:105702. doi: 10.1016/j.bioorg.2022.105702. Epub 2022 Mar 6.

Abstract

On the basis of synergistic effect between topoisomerase (Top) and histone deacetylase (HDAC) inhibitors, a series of novel evodiamine-based Top/HDAC dual inhibitors were designed and synthesized. Systematic structure-activity relationship (SAR) studies led to the discovery of compounds 29b and 45b, which simultaneously inhibited Top and HDAC and exhibited potent antitumor activities against the HCT116 cell line. Compounds 29b and 45b efficiently induced apoptosis with G2 cell cycle arrest and significantly inhibited cellular HDACs in HCT116 cells with good in vitro metabolic stabilities. Collectively, this work provides valuable SAR information and lead compounds for evodiamine-based Top/HDAC dual inhibitors.

Keywords: Antitumor activity; Drug design; Evodiamine; Histone deacetylase; Structure-activity relationship; Topoisomerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors* / pharmacology
  • Histone Deacetylases / metabolism
  • Humans
  • Quinazolines
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Quinazolines
  • evodiamine
  • Histone Deacetylases