2. Academic Validation
  3. Design, synthesis and biological evaluation of 3-aryl-7-hydroxy scopoletin derivatives as autophagy activators against tumorigenesis

Design, synthesis and biological evaluation of 3-aryl-7-hydroxy scopoletin derivatives as autophagy activators against tumorigenesis

  • Eur J Med Chem. 2022 Dec 15:244:114805. doi: 10.1016/j.ejmech.2022.114805.
Xiang Lu 1,  Chaoran Zhu 2,  Chongwei Zhang 3,  Xiujun Li 2,  Zhenqiang Yu 2,  Zhenzhong Zhang 4,  Xiufang Shi 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China.
  • 2 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 3 Henan Institute of Veterinary Drug and Feed Control, Zhengzhou, 450008, China.
  • 4 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China. Electronic address: zhangzhenzhong@zzu.edu.cn.
  • 5 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: xfshi@zzu.edu.cn.
PMID: 36242987 DOI: 10.1016/j.ejmech.2022.114805
Abstract

A natural product scopoletin, which also contains an ortho-substituted phenolic structure in its skeleton, was found in some medicinal Plants. In this study, to develop scopoletin-based Autophagy activators, various aryl substitutes were introduced at the 3-positon or 4-position of scopoletin skeleton with the ortho-substituted phenolic structure retained. A total of twenty-three derivatives were synthesized, evaluated for their antiproliferation activity against four Cancer cells (MCF-7, HeLa, PC3, and MGC803), and discussed for their structure-activity relationships (SARs). Among these derivatives, 5c was the most potent compound with an excellent improvement of antiproliferation activity against PC3 and MGC803 cells compared to the parental scopoletin. 5c displayed up to 17.9- and 5.7-fold improvement of antiproliferation activities against PC3 and MGC803 cells compared to 5-FU (IC50 = 0.14 μM vs IC50 = 2.50 μM, IC50 = 1.02 μM vs IC50 = 5.81 μM), respectively. Moreover, 5c showed excellent selectivity between Cancer cells and one normal cell (GES-1). Further mechanism investigations confirmed that 5c inhibited PC3 and MGC803 cell proliferation via inducing Autophagy. Interestingly, 5c also induced mitochondria-mediated Apoptosis in PC3 cells but not in MGC803 cells. Moreover, 5c possessed the ability to suppress colony formation and migration of PC3 and MGC803 cells. In addition, 5c arrested the cell cycle at the G2/M phase of PC3 cells.

Keywords

Anticancer; Antiproliferation; Apoptosis; Autophagy; Scopoletin.

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