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The discovery and optimization of novel dual inhibitors of topoisomerase ii and histone deacetylase |
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| Authors: | 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 |
| Institution: | 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;2. Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, PR China;3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, Shanghai 201203, PR China;4. Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China;5. Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China |
| 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 24d 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: | Podophyllotoxin HDAC Topoisomerase II Cancer Hybrid Synergistic effect |
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