title: 3-(4-(tert-Octyl)phenoxy)propane-1,2-diol suppresses inflammatory responses via inhibition of multiple kinases.
abstract: Novel anti-inflammatory compounds were synthesised by derivatization of militarin, a compound isolated from Cordyceps militaris that is an ethnopharmacologically well-known herbal medicine with multiple benefits such as anti-cancer, anti-inflammatory, anti-obesity, and anti-diabetic properties. In this study, we explored the in vitro and in vivo anti-inflammatory potencies of these compounds during inflammatory responses, their inhibitory mechanisms, and acute toxicity profiles. To do this, we studied inflammatory conditions using in vitro lipopolysaccharide-treated macrophages and several in vivo inflammatory models such as dextran sodium sulphate (DSS)-induced colitis, EtOH/HCl-induced gastritis, and arachidonic acid-induced ear oedema. Methods used included real-time PCR, immunoblotting analysis, immunoprecipitation, reporter gene assays, and direct kinase assays. Of the tested compounds, compound III showed the highest nitric oxide (NO) inhibitory activity. This compound also inhibited the production of prostaglandin (PG)E(2) at the transcriptional level by suppression of Syk/NF-κB, IKKɛ/IRF-3, and p38/AP-1 pathways in lipopolysaccharide (LPS)-activated RAW264.7 cells and peritoneal macrophages. Consistent with these findings, compound III strongly ameliorated inflammatory symptoms in colitis, gastritis, and ear oedema models. In acute toxicity tests, there were no significant differences in body and organ weights, serum parameters, and stomach lesions between the untreated and compound III-treated mice. Therefore, this compound has the potential to be served as a lead chemical for developing a promising anti-inflammatory drug candidate with multiple kinase targets.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.forename: Jaegal
authors.initials: J
authors.lastname: Shim
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Yang
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Byeon
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Ho Sik
authors.initials: HS
authors.lastname: Rho
authors.forename: Haeil
authors.initials: H
authors.lastname: Park
authors.forename: Gi-Ho
authors.initials: GH
authors.lastname: Sung
authors.forename: Tae Woong
authors.initials: TW
authors.lastname: Kim
authors.forename: Man Hee
authors.initials: MH
authors.lastname: Rhee
authors.forename: Jae Youl
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011409:Propylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: C572457:3-(4-(tert-octyl)phenoxy)propane-1,2-diol; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D011409:Propylene Glycols; D009569:Nitric Oxide; D010770:Phosphotransferases; D015232:Dinoprostone