2. Academic Validation
  3. Novel 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives as potent anti-gastric cancer agents: Design, synthesis and structural optimization

Novel 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives as potent anti-gastric cancer agents: Design, synthesis and structural optimization

  • Eur J Med Chem. 2019 Jan 1:161:493-505. doi: 10.1016/j.ejmech.2018.10.058.
Tao-Qian Zhao 1,  Yuan-Di Zhao 1,  Xin-Yang Liu 1,  Zhong-Hua Li 1,  Bo Wang 1,  Xin-Hui Zhang 1,  Ya-Quan Cao 1,  Li-Ying Ma 2,  Hong-Min Liu 3
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China.
  • 2 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China. Electronic address: maliying@zzu.edu.cn.
  • 3 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China. Electronic address: liuhm@zzu.edu.cn.
PMID: 30388465 DOI: 10.1016/j.ejmech.2018.10.058
Abstract

To explore anti-gastric Cancer agents with high efficacy and selectivity, we report the design, synthesis and optimization of a novel series of 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives starting from the compound PCA-15 reported by us previously. Most of the target compounds demonstrated significant antiproliferative effects on MGC803 Cancer cell line, and more potent than the positive control (PCA-15 and 5-Fu). Among them, compound 6o was identified to be the most active compound against MGC803 cell line with an IC50 value of 0.84 μM. Additionally, high selectivity was also observed between Cancer and normal cells (23.35 μM against GES-1). Further mechanism studies confirmed that compound 6o could inhibit colony formation and migration, induce the Apoptosis of MGC803 cells through both the mitochondrial-mediated intrinsic pathway and death receptor-mediated extrinsic pathway, which were evidenced by the up-regulation of Bax, cleaved-caspase 9/3/8, cleaved PARP and down-regulation of Bcl-2. Our systematic studies implied a new scaffold targeting gastric Cancer cells for further development of small-molecule compounds with improved potency and selectivity.

Keywords

3-(2,6,9-Trisubstituted-9H-purine)-8-chalcone; Anti-gastric cancer activity; Apoptosis; Migration; Structural optimization.

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