Concise syntheses and anti-inflammatory effects of isocorniculatolide B and corniculatolide B and C

초록

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-alpha, IL-1(i and IL-6 by inhibiting of NF-KB 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-KB to the same extent as Bay 11-7082, a potent IKB kinase inhibitor. These results suggest that corniculatolide B might have therapeutic potential in inflammatory bowel disease via NF-KB signaling pathway.

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