A 3-styrylchromone converted from trimebutine 3D pharmacophore possesses dual suppressive effects on RAGE and TLR4 signaling pathways

Miwa Okazawa, Takahiro Oyama, Hideaki Abe, Hiroaki Yamazaki, Atsushi Yoshimori, Mitsutoshi Tsukimoto, Kazumi Yoshizawa, Koichi Takao, Yoshiaki Sugita, Takanori Kamiya, Fumiaki Uchiumi, Hiroshi Sakagami, Takehiko Abe, Sei ichi Tanuma

Research output: Contribution to journalArticlepeer-review

Abstract

Receptor for advanced glycation end-products (RAGE) and Toll-like receptors (TLRs) are potential therapeutic targets in the treatment of acute and chronic inflammatory diseases. We previously reported that trimebutine, a spasmolytic drug, suppresses RAGE pro-inflammatory signaling pathway in macrophages. The aim of this study was to convert trimebutine to a new small molecule using in silico 3D pharmacophore similarity search, and dissect the mechanistic anti-inflammatory basis. Of note, a unique 3-styrylchromone (3SC), 7-methoxy-3-trimethoxy-SC (7M3TMSC), converted from trimebutine 3D pharmacophore potently suppressed both high mobility group box 1-RAGE and lipopolysaccharide-TLR4 signaling pathways in macrophage-like RAW264.7 cells. More importantly, 7M3TMSC inhibited the phosphorylation of extracellular signaling-regulated kinase 1 and 2 (ERK1/2) and downregulated the production of cytokines, such as interleukin-6. Furthermore, 3D pharmacophore-activity relationship analyses revealed that the hydrogen bond acceptors of the trimethoxy groups in a 3-styryl moiety and the 7-methoxy-group in a chromone moiety in this compound are significant in the dual anti-inflammatory activity. Thus, 7M3TMSC may provide an important scaffold for the development of a new type of anti-inflammatory dual effective drugs targeting RAGE/TLR4-ERK1/2 signaling.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume566
DOIs
Publication statusPublished - 20 Aug 2021

Keywords

  • HMGB1
  • Inflammation
  • RAGE
  • Styrylchromone
  • TLR

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