A new series of 21 fused coumarin derivatives was designed and synthesized. Their in vitro antiinflammatory effects as inhibitors of lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW 264.7 macrophages have been evaluated. 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 PGE2 production would not caused by cytotoxicity. Compounds 1f and 1p were the most active PGE2 inhibitors with IC50 values of 0.89 μM 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 IC50 values against COX-2 enzyme were 0.67 μM and 0.85 μM, respectively, more potent than etoricoxib. The selectivity indexes of compounds 1f and 1p against COX-2 than COX-1 were 41.1 and 42.5, respectively. Compound 1f showed strong inhibitory effect 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 analogue 1u were the most potent NO inhibitors with one-digit micromolar IC50 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.

Design and synthesis of tricyclic and tetracyclic fused coumarin sulfonate derivatives, and their inhibitory effects on LPS-induced nitric oxide and PGE2 productions in RAW 264.7 macrophages

253rd National Meeting (2017)

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