title: Synthesis and anti-inflammatory evaluations of β-lapachone derivatives.
abstract: β-Lapachone (β-LAPA), a natural product from the lapacho tree in South America, is a potential chemotherapeutic agent that exhibit a wide variety of pharmacological effects such as anti-virus, anti-parasitic, anti-cancer, and anti-inflammatory activities. In order to discover novel anti-inflammatory agents, we have synthesized a series of β-LAPA derivatives for evaluation. Among them, 4-(4-methoxyphenoxy)naphthalene-1,2-dione (6b) was found to be able to inhibit NO and TNF-α released in LPS-induced Raw 264.7 cells. Inhibition of iNOS and COX-2 was also observed in compound 6b treated cells. Mechanism studies indicated that 6b exhibited anti-inflammatory properties by suppressing the release of pro-inflammatory factors through down-regulating NF-κB activation. In addition, it suppressed NF-κB translocation by inhibiting the phosphorylation of p38 kinase. Our results also indicate that the inhibitory effect of 6b on LPS-stimulated inflammatory mediator production in Raw 264.7 cell is associated with the suppression of the NF-κB and MAPK signaling pathways. A low cytotoxicity (IC(50) = 31.70 μM) and the potent anti-inflammatory activity exhibited by compound 6b make this compound a potential lead for developing new anti-inflammatory agents. Further structural optimization of compound 6b is on-going.
authors.affiliation: Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
authors.forename: Chih-Hua
authors.initials: CH
authors.lastname: Tseng
authors.forename: Chih-Mei
authors.initials: CM
authors.lastname: Cheng
authors.forename: Cherng-Chyi
authors.initials: CC
authors.lastname: Tzeng
authors.forename: Shin-I
authors.initials: SI
authors.lastname: Peng
authors.forename: Chiao-Li
authors.initials: CL
authors.lastname: Yang
authors.forename: Yeh-Long
authors.initials: YL
authors.lastname: Chen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015536:Down-Regulation; D051379:Mice; D008968:Molecular Conformation; D016328:NF-kappa B / Q000378:metabolism; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C581374:4-(4-methoxyphenoxy)naphthalene-1,2-dione; D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D009285:Naphthoquinones; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C014638:beta-lapachone; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases