Tulipiferamide A, an Alkamide from Liriodendron tulipifera, Exhibits an Anti-Inflammatory Effect via Targeting IKKβ Phosphorylation

Three new alkamides, tulipiferamides A-C (1-3, respectively), and 30 known compounds (4-33) were obtained from the roots of Liriodendron tulipifera (Magnoliaceae). Dehydrotemisin (4), an elemane sesquiterpene lactone, was isolated for the first time from nature. The structures were deduced by the interpretation of NMR spectroscopic and MS spectral data. The geometries of the double bonds in tulipiferamides A-C (1-3, respectively) were determined on the basis of ¹H-¹H coupling constants and ¹³C chemical shifts. The presence of the alkamide type in this plant is reported for the first time. An analysis of the inflammatory response revealed that seven compounds (1, 4, 7, 9, 14, 23, and 27) suppressed the nitric oxide production induced by LPS in RAW264.7 macrophages. Furthermore, tulipiferamide A (1) inhibits NF-κB activation by selectively targeting IKKβ, an upstream kinase of NF-κB, resulting in the suppression of inflammatory mediators, including iNOS, COX-2, IL-1β, TNFα, and IL-6. Our results provide a rationale for the further development of tulipiferamide A as a selective IKKβ inhibitor to modulate inflammatory diseases.