Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2‑Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents

• Published in: Journal of medicinal chemistry Vol. 58; no. 13; pp. 5242 - 5255
• Main Authors: Peng, Shoujiao, Zhang, Baoxin, Meng, Xianke, Yao, Juan, Fang, Jianguo
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.07.2015; Amer Chemical Soc
• Subjects: Animals; Antioxidants - pharmacology; Apoptosis - drug effects; Blotting, Western; Cell Proliferation - drug effects; Cells, Cultured; Chemistry, Medicinal; Cinnamates - chemical synthesis; Cinnamates - pharmacology; Coumaric Acids - chemical synthesis; Coumaric Acids - pharmacology; Cytoprotection - drug effects; Dioxolanes - chemistry; Hydrogen Peroxide - pharmacology; Life Sciences & Biomedicine; Molecular Structure; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - pharmacology; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress - drug effects; PC12 Cells; Pharmacology & Pharmacy; Piperidones - chemical synthesis; Piperidones - pharmacology; Rats; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Science & Technology; Signal Transduction - drug effects; Structure-Activity Relationship; CANCER-CELLS; OXIDATIVE STRESS; CYTOSOLIC THIOREDOXIN REDUCTASE; PIPER-LONGUM L; BIOLOGICAL EVALUATION; ALPHA,BETA-UNSATURATED IMIDES; MEDIATED APOPTOSIS; PC12 CELLS; NEURODEGENERATIVE DISEASES; LIVING CELLS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00410

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.