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  3. Thiosemicarbazone-based lead optimization to discover high-efficiency and low-toxicity anti-gastric cancer agents

Thiosemicarbazone-based lead optimization to discover high-efficiency and low-toxicity anti-gastric cancer agents

  • Eur J Med Chem. 2020 Aug 1;199:112349. doi: 10.1016/j.ejmech.2020.112349.
Xin-Hui Zhang 1,  Bo-Wang 1,  Yuan-Yuan Tao 1,  Qin Ma 1,  Hao-Jie Wang 1,  Zhang-Xu He 1,  Hui-Pan Wu 1,  Yi-Han Li 1,  Bing Zhao 2,  Li-Ying Ma 3,  Hong-Min Liu 4
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China.
  • 2 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China. Electronic address: [email protected].
  • 3 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China. Electronic address: [email protected].
  • 4 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China. Electronic address: [email protected].
PMID: 32438199 DOI: 10.1016/j.ejmech.2020.112349
Abstract

In this paper, a series of thiosemicarbazone derivatives containing different aromatic heterocyclic groups were synthesized and the tridentate donor system of the lead compound was optimized. Most of the target compounds showed improved antiproliferative activity against MGC803 cells. SAR studies revealed that compound 5d displayed significant advantages in inhibition effect with an IC50 value of 0.031 μM, and better selectivity between Cancer and normal cells than 3-AP and DpC (about 15- and 5-fold improved respectively). Besides, compound 5d showed selective antiproliferative activity in not only other Cancer cells but also different gastric Cancer cell lines. In-depth mechanism studies showed that compound 5d could induce mitochondria-related Apoptosis which might be related to the elevation of intracellular ROS level, and cause cell cycle arrest at S phase. Moreover, 5d could evidently suppress the cell migration and invasion by blocking the EMT (epithelial-mesenchymal transition) process. Consequently, our studies provided a lead optimization strategy of thiosemicarbazone derivatives which would contribute to discover high-efficiency and low-toxicity agents for the treatment of gastric Cancer.

Keywords

Gastric cancer; Lead optimization; Migration; Thiosemicarbazone.

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