The indole-hydantoin derivative exhibits anti-inflammatory activity by preventing the transactivation of NF-κB through the inhibition of NF-κB p65 phosphorylation at Ser276

• Published in: International immunopharmacology 2021-11, Vol.100, p.108092-108092, Article 108092
• Main Authors: Lin, Xin, Tago, Kenji, Okazaki, Nozomi, So, Takanori, Takahashi, Kyoko, Mashino, Tadahiko, Tamura, Hiroomi, Funakoshi-Tago, Megumi
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Chemokine CXCL1 - genetics; Chemokine CXCL1 - metabolism; Cyclic AMP response element-binding protein; Gene expression; Humans; Hydantoin; Hydantoins - chemical synthesis; Hydantoins - pharmacology; Indole-hydantoin derivative; Indoles; Indoles - chemical synthesis; Indoles - pharmacology; Inflammation; Inflammation - chemically induced; Inflammation - genetics; Inflammation - metabolism; Inflammation - prevention & control; Lipopolysaccharides; Lipopolysaccharides - toxicity; LPS; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Mice; Monocyte chemoattractant protein 1; NF-κB; NF-κB protein; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Nuclear transport; Phosphorylation; phosphorylation: Ser276; RAW 264.7 Cells; Signal Transduction; THP-1 Cells; Transcription; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transcriptional Activation - drug effects; Translocation; U937 Cells
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.108092

•The indole-hydantoin derivative IH-1 inhibits LPS-induced inflammation.•IH-1 prevents the LPS-induced transactivation of NF-κB.•IH-1 suppresses the LPS-induced phosphorylation of NF-κB p65 at Ser276. Indole- and hydantoin-based derivatives both exhibit anti-inflammatory activity, suggesting that the structures of indole and hydantoin are functional for this activity. In the present study, we synthesized two types of indole-hydantoin derivatives, IH-1 (5-(1H-indole-3-ylmethylene) imidazolidine-2,4-dione) and IH-2 (5-(1H-indole-3-ylmethyl) imidazolidine-2,4-dione) and examined their effects on LPS-induced inflammatory responses in murine macrophage-like RAW264.7 cells. LPS-induced inflammatory responses were not affected by indole, hydantoin, or IH-2. In contrast, IH-1 significantly inhibited the LPS-induced production of nitric oxide (NO) and secretion of CCL2 and CXCL1 by suppressing the mRNA expression of inducible NO synthase (iNOS), CCL2, and CXCL1. IH-1 markedly inhibited the LPS-induced activation of NF-κB without affecting the degradation of IκBα or nuclear translocation of NF-κB. IH-1 markedly attenuated the transcriptional activity of NF-κB by suppressing the LPS-induced phosphorylation of the NF-κB p65 subunit at Ser276. Furthermore, IH-1 prevented the LPS-induced interaction of NF-κB p65 subunit with a transcriptional coactivator, cAMP response element-binding protein (CBP). Collectively, these results revealed the potential of the novel indole-hydantoin derivative, IH-1 as an anti-inflammatory drug.