2. Academic Validation
  3. The discovery and optimization of novel dual inhibitors of topoisomerase II and histone deacetylase

The discovery and optimization of novel dual inhibitors of topoisomerase II and histone deacetylase

  • Bioorg Med Chem. 2013 Nov 15;21(22):6981-95. doi: 10.1016/j.bmc.2013.09.023.
Xuan Zhang 1,  Bin Bao,  Xiuhua Yu,  Linjiang Tong,  Yu Luo,  Qingqing Huang,  Mingbo Su,  Li Sheng,  Jia Li,  Hong Zhu,  Bo Yang,  Xiongwen Zhang,  Yi Chen,  Wei Lu
Affiliations

Affiliation

  • 1 Institute of Drug Discovery and Development, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
PMID: 24095018 DOI: 10.1016/j.bmc.2013.09.023
Abstract

A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of Topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in Cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24 d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity.

Keywords

Cancer; HDAC; Hybrid; Podophyllotoxin; Synergistic effect; Topoisomerase II.

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