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

Xuan Zhang; 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

doi:10.1016/j.bmc.2013.09.023

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. Epub 2013 Sep 18.

Authors

Xuan Zhang¹, 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

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Topoisomerases, Type II / chemistry
DNA Topoisomerases, Type II / metabolism*
Drug Evaluation, Preclinical
Enzyme Activation / drug effects
HCT116 Cells
Histone Deacetylase Inhibitors* / chemical synthesis
Histone Deacetylase Inhibitors* / chemistry
Histone Deacetylase Inhibitors* / pharmacology
Histone Deacetylases / chemistry
Histone Deacetylases / genetics
Histone Deacetylases / metabolism*
Humans
Hydroxamic Acids / chemistry
Hydroxamic Acids / toxicity
Phenylenediamines / chemical synthesis
Phenylenediamines / chemistry
Phenylenediamines / pharmacology*
Podophyllotoxin / analogs & derivatives*
Podophyllotoxin / chemical synthesis
Podophyllotoxin / chemistry
Podophyllotoxin / pharmacology
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Structure-Activity Relationship
Topoisomerase II Inhibitors* / chemical synthesis
Topoisomerase II Inhibitors* / chemistry
Topoisomerase II Inhibitors* / pharmacology
Vorinostat

Substances

Histone Deacetylase Inhibitors
Hydroxamic Acids
Phenylenediamines
Recombinant Proteins
Topoisomerase II Inhibitors
Vorinostat
Histone Deacetylases
DNA Topoisomerases, Type II
Podophyllotoxin