2. Academic Validation
  3. Synthesis and discovery of Baylis-Hillman adducts as potent and selective thioredoxin reductase inhibitors for cancer treatment

Synthesis and discovery of Baylis-Hillman adducts as potent and selective thioredoxin reductase inhibitors for cancer treatment

  • Bioorg Med Chem. 2023 Feb 1:79:117169. doi: 10.1016/j.bmc.2023.117169.
Yi-Lin He 1,  Miao Zhong 2,  Zi-Long Song 1,  Yu-Kai Shen 3,  Lanning Zhao 4,  Jianguo Fang 2
Affiliations

Affiliations

  • 1 Natural Medicine Research & Development Center, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, China; State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
  • 2 State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
  • 3 Lizhi College, Xi'an Jiaotong University, No. 28, Xianning West Road, Xi'an, Shaanxi 710049, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of the Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: zhaoln@ucas.ac.cn.
PMID: 36657375 DOI: 10.1016/j.bmc.2023.117169
Abstract

The selenoprotein thioredoxin reductase (TrxR) is of paramount importance in maintaining cellular redox homeostasis, and aberrant upregulation of TrxR is frequently observed in various cancers due to their elevated oxidative stress in cells. Thus, it seems promising and feasible to target the ablation of intracellular TrxR for the treatment of cancers. We report herein the design and synthesis of a series of Baylis-Hillman adducts, and identified a typical adduct that possesses the superior cytotoxicity against HepG2 cells over Other types of Cancer cells. The biological investigation shows the selected typical adduct selectively targets TrxR in HepG2 cells, which thereafter results in the collapse of intracellular redox homeostasis. Further mechanistic studies reveal that the selected typical adduct arrests the cell cycle in G1/G0 phase. Importantly, the malignant metastasis of HepG2 cells is significantly restrained by the selected typical adduct. With well-defined molecular target and mechanism of action, the selected typical adduct, even Other Baylis-Hillman skeleton-bearing compounds, merits further development as candidate or ancillary agent for the treatment of various cancers.

Keywords

Anticancer; Baylis-Hillman adducts; Redox homeostasis; Thioredoxin reductase.

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