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

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.
Fugui Zhu 1,  Xiangguo Meng 2,  Huixin Liang 1,  Chunquan Sheng 3,  Guoqiang Dong 3,  Dan Liu 4,  Shanchao Wu 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, People's Republic of China; Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
  • 2 College of Pharmacy, Shanghai University of Medicine and Health Sciences, 279 Zhouzhugong Road, Shanghai 201318, People's Republic of China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, People's Republic of China. Electronic address: liudan@syphu.edu.cn.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Electronic address: wushanchao07_2@smmu.edu.cn.
PMID: 35286923 DOI: 10.1016/j.bioorg.2022.105702
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.

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