Bioactivity Study of Tricyclic and Tetracyclic Genipin Derivatives as Anti-inflammatory Agents

  • Bioorg Chem. 2022 Sep;126:105881. doi: 10.1016/j.bioorg.2022.105881.
Sin-Min Li  1 ,  Chia-Yin Chiang  2 ,  Wei-Zheng Zeng  3 ,  Cheng-Yen Chung  4 ,  Ching-Chun Tseng  2 ,  Yu-Pei Hu  5 ,  Yu-Ching Lin  5 ,  Guan-Jhong Huang  6 ,  Ichiro Arai  7 ,  Der-Yen Lee  8 ,  Shuo-En Tsai  2 ,  Fung Fuh Wong  9
Affiliations
  • 1. Institute of New Drug Development, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 2. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 3. Master Program for Pharmaceutical Manufacture, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 4. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan; Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 5. Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
  • 6. Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan.
  • 7. Department of Pharmaceutical Science, Nihon Pharmaceutical University, 10281, Komuro, Inamachi, Kita-Adachigun, Saitama, Japan.
  • 8. Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung City 40402, Taiwan.
  • 9. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan; School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan. Electronic address: [email protected].
PMID: 35636127 DOI: 10.1016/j.bioorg.2022.105881
Abstract

A series of genipin derivatives included tricyclic cyclopentaimidazopyridine, cyclopentapyridopyrimidine, octahydrocyclopentapyridodiazepine, and tetracyclic decahydrobenzoimidazocyclopentapyridine were synthesized and developed as anti-inflammatory agents. All of them were tested against NO production in LPS-induced RAW264.7 cells. Based on IC50 data and the SAR study, we found that tricyclic cyclopentaimidazopyridines 3d-f and 7-9 presented the better inhibitory activities (≦ 28.1 μM) in comparison with the reference standard Indomethacin (166 μM). On the Other hand, all of them showed inactivity for in vitro cyclooxygenase COX-2 inhibition assays and compounds 8 and 9 possessed the cell toxity. To explore the further anti-inflammatory mechanism, Western blot analysis was carried out. Furthermore, compound 3d shown better bioactivity than Indomethacin. The suppression of NF-κB signal pathway by compound 3d was also determined. To sum-up, compound 3d would be the potential anti-inflammatory lead compound.

Keywords
Anti-inflammation; Cyclopentaimidazopyridine; Cyclopentapyridopyrimidine; Genipin; Iridoids.
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