Concise syntheses and anti-inflammatory effects of isocorniculatolide B and corniculatolide B and C
- Authors
- Kim, Taewoo; Kwon, Hyuk; Lee, Da-Young; Kim, Dong-Jun; Jeon, Yoonsu; Shin, Hyeyoung; Kim, Hyun Su; Hur, Joonseong; Lim, Changjin; Kim, Eun-Hee; Shin, Dongyun; Kim, Seok-Ho
- Issue Date
- Nov-2021
- Publisher
- Academic Press Inc.
- Keywords
- Anti-inflammatory activity; Corniculatolide B; IBD; Isomeric corniculatolides; NF-κB; Total synthesis
- Citation
- Bioorganic Chemistry, v.116
- Journal Title
- Bioorganic Chemistry
- Volume
- 116
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/82629
- DOI
- 10.1016/j.bioorg.2021.105398
- ISSN
- 0045-2068
- Abstract
- The first total syntheses of isocorniculatolide B, corniculatolide B, and corniculatolide C, consisting of isomeric corniculatolide skeletons, have been accomplished in a divergent manner. The key features of the synthesis involve the construction of diaryl ether linkages by nucleophilic aromatic substitution, installation of a C14-substituted alkyl side chain via a sequence of Baeyer-Villiger reaction and Claisen rearrangement, and efficient construction of corniculatolide and isocorniculatolide frameworks, including 17-membered (exterior) macrolactone skeletons from a versatile diaryl ether intermediate by Mitsunobu macrolactonization. Moreover, we prepared the structural congeners of isomeric corniculatolides via diverted total synthesis approach including desmethyl analogues and related dimeric macrolides. The anti-inflammatory activities of the synthesized natural products, analogues and synthetic intermediates were also investigated. In particular, corniculatolide B significantly inhibited the protein expression of COX-2 and the mRNA expressions of TNF-α, IL-1β and IL-6 by inhibiting of NF-κB signaling in intestinal epithelial cells induced by lipopolysaccharide treatment. It also significantly inhibited the promoter activity and the phosphorylation of subunits p50 and p65 of NF-κB to the same extent as Bay 11-7082, a potent IκB kinase inhibitor. These results suggest that corniculatolide B might have therapeutic potential in inflammatory bowel disease via NF-κB signaling pathway. © 2021 Elsevier Inc.
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