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

Xin Lin, Kenji Tago, Nozomi Okazaki, Takanori So, Kyoko Takahashi, Tadahiko Mashino, Hiroomi Tamura, Megumi Funakoshi-Tago

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number108092
JournalInternational Immunopharmacology
Volume100
DOIs
Publication statusPublished - 2021 Nov

Keywords

  • Indole-hydantoin derivative
  • LPS
  • NF-κB
  • phosphorylation: Ser276

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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