Synthesis of piperlongumine analogues and discovery of nuclear factor erythroid 2-related factor 2 (Nrf2) activators as potential neuroprotective agents.

Abstract

The cellular antioxidant system plays key roles in blocking or retarding the pathogenesis of adult neurodegenerative disorders as elevated oxidative stress has been implicated in the pathophysiology of such diseases. Molecules with the ability in enhancing the antioxidant defense thus are promising candidates as neuroprotective agents. We reported herein the synthesis of piperlongumine analogues and evaluation of their cytoprotection against hydrogen peroxide- and 6-hydroxydopamine-induced neuronal cell oxidative damage in the neuron-like PC12 cells. The structure-activity relationship was delineated after the cytotoxicity and protection screening. Two compounds (4 and 5) displayed low cytotoxicity and confer potent protection of PC12 cells from the oxidative injury via upregulation of a panel of cellular antioxidant molecules. Genetically silencing the transcription factor Nrf2, a master regulator of the cellular stress responses, suppresses the cytoprotection, indicating the critical involvement of Nrf2 for the cellular action of compounds 4 and 5 in PC12 cells.

• Authors: Shoujiao Peng, Baoxin Zhang, Xianke Meng, Juan Yao, Jianguo Fang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 13 Pg. 5242-55 (Jul 09 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26079183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(3-(3,4,5-trimethoxyphenyl)acryloyl)piperidin-2-one
• 1-(3-(4-methoxyphenyl)acryloyl)pyrrolidin-2-one
• Antioxidants
• Cinnamates
• Coumaric Acids
• Dioxolanes
• NF-E2-Related Factor 2
• Neuroprotective Agents
• Piperidones
• RNA, Messenger
• RNA, Small Interfering
• Hydrogen Peroxide
• piperlongumine

Topics

• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cinnamates (chemical synthesis, pharmacology)
• Coumaric Acids (chemical synthesis, pharmacology)
• Cytoprotection (drug effects)
• Dioxolanes (chemistry)
• Hydrogen Peroxide (pharmacology)
• Molecular Structure
• NF-E2-Related Factor 2 (antagonists & inhibitors, genetics, metabolism)
• Neuroprotective Agents (chemical synthesis, pharmacology)
• Oxidative Stress (drug effects)
• PC12 Cells
• Piperidones (chemical synthesis, pharmacology)
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Rats
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Structure-Activity Relationship