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  3. Design, synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors

Design, synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors

  • Bioorg Med Chem. 2018 Aug 7;26(14):3958-3966. doi: 10.1016/j.bmc.2018.06.016.
Jiwei Chen 1,  Dan Li 1,  Wenlu Li 1,  Jingxian Yin 1,  Yueying Zhang 1,  Zigao Yuan 2,  Chunmei Gao 3,  Feng Liu 4,  Yuyang Jiang 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Tsinghua University, Beijing 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, PR China.
  • 2 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, PR China; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, PR China. Electronic address: yzg12@tsinghua.org.cn.
  • 3 College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen 518060, PR China.
  • 4 Department of Chemistry, Tsinghua University, Beijing 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, PR China. Electronic address: liu.feng@sz.tsinghua.edu.cn.
  • 5 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China.
PMID: 29954683 DOI: 10.1016/j.bmc.2018.06.016
Abstract

Multitarget inhibitors design has generated great interest in Cancer treatment. Based on the synergistic effects of Topoisomerase and histone deacetylase inhibitors, we designed and synthesized a new series of acridine hydroxamic acid derivatives as potential novel dual Topo and HDAC inhibitors. MTT assays indicated that all the hybrid compounds displayed good antiproliferative activities with IC50 values in low micromolar range, among which compound 8c displayed potent activity against U937 (IC50 = 0.90 μM). In addition, compound 8c also displayed the best HDAC inhibitory activity, which was several times more potent than HDAC Inhibitor SAHA. Subsequent studies indicated that all the compounds displayed Topo II inhibition activity at 50 μM. Moreover, compound 8c could interact with DNA and induce U937 Apoptosis. This study provides a suite of compounds for further exploration of dual Topo and HDAC inhibitors, and compound 8c can be a new dual Topo and HDAC inhibitory Anticancer agent.

Keywords

Anticancer; Drug design; Dual inhibitor; Histone deacetylase; Topoisomerase.

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