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Developing dietary curcumin mono-carbonyl piperidinone analogs as Nrf2-dependent cytoprotectors against oxidative

Xue-Feng Liu1, Qi Wang2, Jia-Fang Zheng2

  • 1State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China; School of Pharmacy, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China; College of Pharmacy, Gansu University of Traditional Chinese Medicine, 35 Dingxi East Road, Gansu, 730000, China.

Free Radical Biology & Medicine
|May 13, 2022
PubMed

Insights

Researchers developed novel Nrf2 activators inspired by curcumin. The lead compound, CN-2F, demonstrated superior cytoprotective effects against oxidative stress, offering a promising strategy for disease prevention.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Biochemistry

Background:

  • Oxidative stress contributes to diseases like cancer and inflammation.
  • Nuclear factor erythroid-2 related factor 2 (Nrf2) plays a crucial role in cellular defense against oxidative damage.
  • Curcumin is a known Nrf2 activator and chemopreventive agent, but more potent analogs are sought.

Purpose of the Study:

  • To design and synthesize novel Nrf2-dependent cytoprotectors with enhanced activity compared to curcumin.
  • To investigate the structure-activity relationships of curcumin-inspired mono-carbonyl piperidinone analogs.
  • To elucidate the molecular mechanisms underlying the cytoprotective effects of the lead compound.

Main Methods:

  • Design and synthesis of curcumin-inspired piperidinone analogs with varied substituents.
  • Evaluation of cytoprotective activity in HepG2 cells against tert-butyl hydroperoxide-induced oxidative damage.
  • Mechanistic studies involving Keap1 modification, Nrf2 signaling pathway activation (including JNK, ERK, p38 phosphorylation), and Nrf2 degradation inhibition.

Main Results:

  • A panel of analogs was synthesized, with the ortho-fluorine-substituted CN-2F identified as a highly promising lead molecule.
  • CN-2F exhibited significantly superior cytoprotective effects compared to curcumin in HepG2 cells.
  • CN-2F covalently modified Keap1 at Cys-151 and Cys-288, activating Nrf2 signaling and inhibiting its degradation.

Conclusions:

  • CN-2F is a potent Nrf2-dependent cytoprotector, outperforming curcumin.
  • The study reveals key structural determinants for designing effective curcumin-inspired Nrf2 activators.
  • Findings provide valuable insights for developing novel therapeutic strategies against oxidative stress-related diseases.
Keywords:
CurcuminCytoprotectionMichael acceptorNrf2Oxidative stress

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