2. Academic Validation
  3. Design and synthesis of Osthole-based compounds as potential Nrf2 agonists

Design and synthesis of Osthole-based compounds as potential Nrf2 agonists

  • Bioorg Med Chem Lett. 2022 Apr 1;61:128547. doi: 10.1016/j.bmcl.2022.128547.
Weiwei Huang 1,  Yi Huang 1,  Jiayan Cui 1,  Yuhang Wu 1,  Fuli Zhu 1,  Jin Huang 2,  Lei Ma 3
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
  • 2 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: [email protected].
  • 3 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: [email protected].
PMID: 35032608 DOI: 10.1016/j.bmcl.2022.128547
Abstract

A total of 23 compounds based on Osthole skeleton were designed and synthesized. Their agonistic activity for Nrf2 were evaluated by Dual-luciferase Reporter Gene Assay. Most of the compounds showed better activities compared with Osthole, especially O15 and O21. And the median effective concerntration (EC50) values was calculated accordingly, both of which showed remarkable activity for Nrf2. The structure activity relationship study indicated that introduction of the structure of stilbene might be beneficial for enhancement of agonistic properties of Osthole, and the position of the substituent may have a greater effect on the activity than the electron-donating/withdrawing ability of the substituent. Mechanism of the action of selected compound O15 was investigated by molecular docking, cellular thermal shift assay and ubiquitination assay, which suggested the reason why O15 exhibited relatively stronger agonistic activity for Nrf2. Compound O15 and O21 both provided novel methods to investigate Osthole-based compounds as Nrf2 agonists.

Keywords

Agonistic activities; Nrf2; Osthole; Oxidation.

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