Rational Design, Synthesis and Evaluation of Oxazolo[4,5-c]-quinolinone Analogs as Novel Interleukin-33 Inhibitors
- Authors
- Kim, Yujin; Ma, Chao; Park, Seonghu; Shin-, Yujin; Lee, Taeyun; Paek, Jiwon; Kim, Kyong Hoon; Jang, Geonhee; Cho, Haelim; Son, Seyoung; Son, Sang-Hyun; Lee, Ki Yong; Lee, Kiho; Jung, Yong Woo; Jeon, Young Ho; Byun, Youngjoo
- Issue Date
- 15-11월-2021
- Publisher
- WILEY-V C H VERLAG GMBH
- Keywords
- Allergy; Cytokine; Inhibitors; Interleukin-33; Oxazoloquinoline
- Citation
- CHEMISTRY-AN ASIAN JOURNAL, v.16, no.22, pp.3702 - 3712
- Indexed
- SCIE
SCOPUS
- Journal Title
- CHEMISTRY-AN ASIAN JOURNAL
- Volume
- 16
- Number
- 22
- Start Page
- 3702
- End Page
- 3712
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/135733
- DOI
- 10.1002/asia.202100896
- ISSN
- 1861-4728
- Abstract
- Interleukin-33 (IL-33) is an epithelial-derived cytokine that plays an important role in immune-mediated diseases such as asthma, atopic dermatitis, and rheumatoid arthritis. Although IL-33 is considered a potential target for the treatment of allergy-related diseases, no small molecule that inhibits IL-33 has been reported. Based on the structure-activity relationship and in vitro 2D NMR studies employing N-15-labeled IL-33, we identified that the oxazolo[4,5-c]-quinolinone analog 7 c binds to the interface region of IL-33 and IL-33 receptor (ST2), an orphan receptor of the IL-1 receptor family. Compound 7 c effectively inhibited the production of IL-6 in human mast cells in a dose-dependent manner. Compound 7 c is the first low molecular weight IL-33 inhibitor and may be used as a prototype molecule for structural optimization and investigation of the IL-33/ST2 signaling pathway.
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