title: Synthesis of New Tricyclic and Tetracyclic Fused Coumarin Sulfonate Derivatives and Their Inhibitory Effects on LPS-Induced Nitric Oxide and PGE2Productions in RAW 264.7 Macrophages: Part 2.
abstract: The synthesis of a new series of 21 fused coumarin derivatives is described, and the biological evaluation of their in vitro antiinflammatory effects as inhibitors of lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2(PGE2) production in RAW 264.7 macrophages. The target compounds 1a-u were first tested for cytotoxicity to determine a non-toxic concentration for antiinflammatory screening, so that the inhibitory effects against NO and PGE2production would not be caused by cytotoxicity. Compounds 1f and 1p were the most active PGE2inhibitors with IC50values of 0.89 and 0.95 µM, respectively. Western blot and cell-free COX-2 screening showed that their effects were due to inhibition of both COX-2 protein expression and COX-2 enzyme activity. Their IC50values against the COX-2 enzyme were 0.67 and 0.85 µM, respectively, which is more potent than etoricoxib. The selectivity indexes of compounds 1f and 1p against COX-2 compared to COX-1 were 41.1 and 42.5, respectively. Compound 1f showed strong inhibitory effects at 5 µM concentration on COX-2 mRNA expression in LPS-induced RAW 264.7 macrophages. Moreover, the tricyclic compounds 1l and 1n as well as the tetracyclic analog 1u were the most potent NO inhibitors, with one-digit micromolar IC50values. They showed dose-dependent inhibition of inducible nitric oxide synthase (iNOS) protein expression. The tetracyclic derivative 1u was the most potent inhibitor of NO production. It also exhibited a strong inhibitory effect on iNOS mRNA expression in LPS-induced RAW 264.7 macrophages.
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.|Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.|Faculty of Pharmacy, Department of Medicinal Chemistry, University of Mansoura, Mansoura, Egypt.
authors: Mohammed I
authors: MI
authors: El-Gamal
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.|Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
authors: Woo-Seok
authors: WS
authors: Lee
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.|Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
authors: Ji-Sun
authors: JS
authors: Shin
authors: Center for Biomaterials, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Republic of Korea.
authors: Chang-Hyun
authors: CH
authors: Oh
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.|Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
authors: Kyung-Tae
authors: KT
authors: Lee
authors: Department of Chemistry, Hanseo University, Seosan, Republic of Korea.
authors: Jungseung
authors: J
authors: Choi
authors: Department of Chemistry, Hanseo University, Seosan, Republic of Korea.
authors: Nohsun
authors: N
authors: Myoung
authors: Department of Chemistry, Hanseo University, Seosan, Republic of Korea. djbaek@hanseo.ac.kr.
authors: Daejin
authors: D
authors: Baek
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology; D002478:Cells, Cultured; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003374:Coumarins; D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: Antiinflammatory; COX-2; Coumarin sulfonate; NO; PGE2