Premium
Synthesis of New Tricyclic and Tetracyclic Fused Coumarin Sulfonate Derivatives and Their Inhibitory Effects on LPS‐Induced Nitric Oxide and PGE 2 Productions in RAW 264.7 Macrophages: Part 2
Author(s) -
ElGamal Mohammed I.,
Lee WooSeok,
Shin JiSun,
Oh ChangHyun,
Lee KyungTae,
Choi Jungseung,
Myoung Nohsun,
Baek Daejin
Publication year - 2016
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201600243
Subject(s) - chemistry , nitric oxide , cytotoxicity , ic50 , coumarin , nitric oxide synthase , lipopolysaccharide , pharmacology , enzyme , enzyme inhibitor , biochemistry , prostaglandin e2 , inhibitory postsynaptic potential , in vitro , stereochemistry , biology , immunology , endocrinology , organic chemistry
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 E 2 (PGE 2 ) 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 PGE 2 production would not be caused by cytotoxicity. Compounds 1f and 1p were the most active PGE 2 inhibitors with IC 50 values 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 IC 50 values 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 IC 50 values. 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.