2. Academic Validation
  3. Synthesis and bioevaluation of novel stilbene-based derivatives as tubulin/HDAC dual-target inhibitors with potent antitumor activities in vitro and in vivo

Synthesis and bioevaluation of novel stilbene-based derivatives as tubulin/HDAC dual-target inhibitors with potent antitumor activities in vitro and in vivo

  • Eur J Med Chem. 2023 Sep 5;257:115529. doi: 10.1016/j.ejmech.2023.115529.
Huajian Zhu 1,  Wenjian Zhu 1,  Yang Liu 1,  Tian Gao 1,  Jingjie Zhu 1,  Yuchen Tan 1,  Han Hu 1,  Wenhao Liang 1,  Lingyue Zhao 1,  Jian Chen 2,  Zheying Zhu 3,  Jichao Chen 4,  Jinyi Xu 5,  Shengtao Xu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
  • 2 Department of Hepatobiliary Surgery, The First People's Hospital of Kunshan, Suzhou, 215132, PR China.
  • 3 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham, NG7 2RD, UK.
  • 4 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China. Electronic address: chenjichao@njucm.edu.cn.
  • 5 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: jinyixu@china.com.
  • 6 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China; Department of Hepatobiliary Surgery, The First People's Hospital of Kunshan, Suzhou, 215132, PR China. Electronic address: cpuxst@cpu.edu.cn.
PMID: 37269670 DOI: 10.1016/j.ejmech.2023.115529
Abstract

A series of novel stilbene-based derivatives were designed and synthesized as tubulin/HDAC dual-target inhibitors. Among forty-three target compounds, compound II-19k not only exhibited considerable antiproliferative activity in the hematological cell line K562 with IC50 value of 0.003 μM, but also effectively inhibited the growth of various solid tumor cell lines with IC50 values ranging from 0.005 to 0.036 μM. The mechanism studies demonstrated that II-19k could inhibit microtubules and HDACs at the cellular level, block cell cycle arrest at G2 phase, induce cell Apoptosis, and reduce solid tumor cells metastasis. What's more, the vascular disrupting effects of compound II-19k were more pronounced than the combined administration of parent compound 8 and HDAC Inhibitor SAHA. The in vivo antitumor assay of II-19k also showed the superiority of dual-target inhibition of tubulin and HDAC. II-19k significantly suppressed the tumor volume and effectively reduced tumor weight by 73.12% without apparent toxicity. Overall, the promising bioactivities of II-19k make it valuable for further development as an antitumor agent.

Keywords

Antitumor; Dual-target inhibitors; HDAC; Stilbene; Tubulin.

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