2. Academic Validation
  3. Design and synthesis of thiazole-based hydroxamate histone deacetylase inhibitors with potent antitumor efficacy by inducing apoptosis, pyroptosis and cell cycle arrest

Design and synthesis of thiazole-based hydroxamate histone deacetylase inhibitors with potent antitumor efficacy by inducing apoptosis, pyroptosis and cell cycle arrest

  • Sci Rep. 2025 Jul 9;15(1):24589. doi: 10.1038/s41598-025-08474-5.
Zhijian Li # 1,  Huiran Qiu # 2,  Wenxia Lu # 2,  Namin Duan # 1,  Shule Fan 2,  Rui Zhou 1,  Xiangzhi Li 2,  Hua Zhang 3,  Ning Liu 4 5,  Feifei Yang 6
Affiliations

Affiliations

  • 1 International Research Centre for Food and Health, College of Food Science and Technology, Shanghai Ocean University, Shanghai, 201306, China.
  • 2 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China.
  • 3 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China. bio_zhangh@ujn.edu.cn.
  • 4 International Research Centre for Food and Health, College of Food Science and Technology, Shanghai Ocean University, Shanghai, 201306, China. nliu@shou.edu.cn.
  • 5 Marine Biomedical Science and Technology Innovation Platform of Lin-Gang Special Area, Shanghai, 201306, China. nliu@shou.edu.cn.
  • 6 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China. bio_yangff@ujn.edu.cn.
  • # Contributed equally.
PMID: 40628818 DOI: 10.1038/s41598-025-08474-5
Abstract

The dysfunction of HDACs is closely related to tumorigenesis and development, which has emerged as an attractive target for Cancer therapy. In this study, a series of thiazole-containing hydroxamate derivatives were designed and synthesized as novel HDAC inhibitors. Among these inhibitors, compounds 15a and 15d showed excellent inhibitory activities against HDAC1 and HepG2 Cancer cell line, these two compounds increased the levels of acetylated histone H3 and H4. Moreover, 15a and 15d significantly arrested HepG2 cells at the G0/G1 phase. Additionally, these two compounds could induce Apoptosis and Pyroptosis. Moreover, 15a exhibited significant antitumor activity in the HepG2 xenograft model. Molecular docking and molecular dynamics simulation studies revealed the possible interaction mode of compound 15a with HDAC1. Besides, the preliminary pharmacokinetics study of compound 15a in vivo was evaluated. These results suggested that these novel thiazole-based HDAC inhibitors might become a promising scaffold for further structural optimization.

Keywords

Anticancer; Histone deacetylase inhibitor; Hydroxamate; Thiazole.

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