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Meta-substituted piperlongumine derivatives attenuate inflammation in both RAW264.7 macrophages and a mouse model of colitis
- Source :
- Bioorganic Chemistry. 117:105465
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Piperlongumine (PL) has been showed to have multiple pharmacological activities. In this study, we reported the synthesis of three series of PL derivatives, and evaluation of their anti-inflammatory effects in both lipopolysaccharide (LPS)-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. Our results presented that two meta-substituent containing derivatives 1–3 and 1–6, in which γ-butyrolactam replaced α,β-unsaturated δ-valerolactam ring of PL, displayed low cytotoxicity and effective anti-inflammatory activity. Molecular docking also showed that the meta-substituted derivative, compared with the corresponding ortho- or para-substituted derivative, had significant interactions with the amino acid residues of CD14, which was the core receptors recognizing LPS. In vitro and in vivo studies, 1–3 and 1–6 could inhibit the expression of pro-inflammatory cytokines, and the excessive production of reactive nitrogen species and reactive oxygen species. Oral administration of 100 mg/kg/day of 1–3 or 1–6 alleviated the severity of clinical symptoms of colitis in mice, and significantly reduced the colonic tissue damage to protect the colonic tissue from the DSS-induced colitis. These results suggested that meta-substituted derivatives 1–3 and 1–6 were potential anti-inflammatory agents, which may lead to future pharmaceutical development.
- Subjects :
- Lipopolysaccharides
Male
CD14
Inflammation
Pharmacology
Nitric Oxide
Biochemistry
Mice
Structure-Activity Relationship
chemistry.chemical_compound
In vivo
Drug Discovery
medicine
Animals
Colitis
Molecular Biology
Cells, Cultured
Reactive nitrogen species
Piperlongumine
chemistry.chemical_classification
Mice, Inbred BALB C
Reactive oxygen species
Dose-Response Relationship, Drug
Molecular Structure
Macrophages
Dextran Sulfate
Organic Chemistry
Dioxolanes
medicine.disease
In vitro
Molecular Docking Simulation
Disease Models, Animal
RAW 264.7 Cells
chemistry
medicine.symptom
Subjects
Details
- ISSN :
- 00452068
- Volume :
- 117
- Database :
- OpenAIRE
- Journal :
- Bioorganic Chemistry
- Accession number :
- edsair.doi.dedup.....2f40fdaa111f5bc40d87bc6b5e212cb4