lupane and Inflammation

With the purpose to improve anti-inflammatory activity, the impact of introduction of 1,2,5- and 1,3,4-oxadiazole fragments to betulonic acid core as well as hybrids tethered with short ω-amino acids has been studied. The anti-inflammatory activity of synthesized compounds was tested in vivo using models of inflammation induced by concanavalin A and histamine. The majority of new compounds demonstrated higher anti-inflammatory activity compared with starting betulonic acid. To confirm the molecular targets of new derivatives in NRf2 and NFκB pathways the docking at Kelch and BTB active sites of Keap1 as well as IKK was done. The novelty of the present work is the development of new class of low toxic anti-inflammatory substances consisting of amino acid-linked betulonic acid - oxadiazole conjugates. These compounds can be considered as prospective chemopreventive agents.

Topics: Amino Acids; Animals; Anti-Inflammatory Agents; Computer Simulation; Concanavalin A; Disease Models, Animal; Edema; Female; Fibroblasts; Histamine; Inflammation; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Molecular Conformation; Molecular Docking Simulation; NF-E2-Related Factor 2; NF-kappa B; Oxadiazoles; Triterpenes

Impressic acid, 3α,11α-dihydroxylup-20(29)-en-28-oic acid, is a lupane-type triterpenoid isolated from Acanthopanax koreanum, which has been used as a Korean folk medicine for rheumatism, hepatitis, diabetes, and inflammatory disorders. Recently, it was reported that impressic acid has inhibitory effects on the LPS-stimulated pro-inflammatory cytokine production in bone marrow-derived dendritic cells and on the nuclear factor of activated T-cells transcription factor activity. Thus, to investigate whether impressic acid has effects on the inhibition of nuclear factor kappa B (NF-κB) and activation of peroxisome proliferator-activated receptor gamma (PPARγ), luciferase reporter assays were used. The effects on the expression of NF-κB and PPARγ target genes were also examined by reverse transcription-polymerase chain reaction. In this study, impressic acid was found to inhibit tumor necrosis factor (TNF)-α induced NF-κB activity and to up-regulate transcriptional activity of PPARγ.

Topics: Bone Marrow Cells; Cell Survival; Chromans; Cytokines; Dendritic Cells; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eleutherococcus; Hep G2 Cells; Humans; Inflammation; Lipopolysaccharides; Luciferases; NF-kappa B; Plant Leaves; PPAR gamma; Rheumatic Diseases; RNA; Thiazolidinediones; Transcription Factors; Transcriptional Activation; Triterpenes; Troglitazone