2. Academic Validation
  3. Synthesis and bioevaluation of a series of α-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I)

Synthesis and bioevaluation of a series of α-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I)

  • Eur J Med Chem. 2013 Aug:66:364-71. doi: 10.1016/j.ejmech.2013.06.007.
Mei-yang Xi 1,  Zhong-ying Sun,  Hao-peng Sun,  Jian-min Jia,  Zheng-yu Jiang,  Lei Tao,  Ming Ye,  Xi Yang,  Ya-jing Wang,  Xin Xue,  Jing-jie Huang,  Yuan Gao,  Xiao-ke Guo,  Sheng-lie Zhang,  Ying-rui Yang,  Qing-long Guo,  Rong Hu,  Qi-dong You
Affiliations

Affiliation

  • 1 Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
PMID: 23820128 DOI: 10.1016/j.ejmech.2013.06.007
Abstract

When exposed to electrophiles, human colorectal Cancer cells (HCT116) counteract oxidative stress through activating NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. To identify new activators, luciferase reporter gene assay was used to screen in-house database of our laboratory, leading to a novel α-pyrone compound 1 as a hit. 2 with 2-fluoro phenyl group exhibited the strongest ARE inductive activity in the first round structure-activity relationship (SAR) study. Biological studies showed the compound induced nuclear translocation of Nrf2 preceded by phosphorylation of ERK1/2. The data encouraged us to use 2 as lead and 20 derivatives were synthesized to discuss a more detailed SAR, leading to a more potent compound 9, which can be the starting compound for further modification.

Keywords

ARE; Chemopreventive agents; Keap1; Nrf2; α-Pyrone derivative.

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