Synthetic cryptolepine inhibits DNA binding of NF-kappaB

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 1; pp. 43 - 49
• Main Authors: Olajide, Olumayokun A, Heiss, Elke H, Schachner, Daniel, Wright, Colin W, Vollmar, Angelika M, Dirsch, Verena M
• Format: Journal Article
• Language: English
• Published: England 01.01.2007
• Subjects: Alkaloids - chemical synthesis; Alkaloids - pharmacology; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Binding Sites; Binding, Competitive - drug effects; Cell Line; Cells, Cultured; Cryptolepis - chemistry; DNA - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Indole Alkaloids; Indoles - chemical synthesis; Indoles - pharmacology; Lipopolysaccharides - antagonists & inhibitors; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Quinolines - chemical synthesis; Quinolines - pharmacology; Structure-Activity Relationship; Transcription, Genetic - drug effects
• ISSN: 0968-0896

The alkaloid cryptolepine is thought to mediate the anti-inflammatory effects of the climbing shrub, Cryptolepis sanguinoleta. The underlying mechanism of action, however, is largely unknown. In the present study, we show that the synthetic cryptolepine-hydrochloride (2.5-10microM) dose-dependently inhibits lipopolysaccharide (LPS)-induced nitric oxide production in the murine macrophage cell line RAW 264.7. We furthermore demonstrate a strong inhibition of nuclear factor (NF)-kappaB, a transcription factor primarily involved in inflammatory and immune responses, by cryptolepine (2.5-10microM) using a luciferase reporter gene assay in human HEK 293 cells. Examining the individual steps of NF-kappaB activation in the presence of cryptolepine we could exclude an inhibitory effect on degradation of IkappaB or nuclear translocation of NF-kappaB by the alkaloid. However, EMSA of nuclear extracts from LPS-activated RAW cells revealed reduced DNA binding activity of NF-kappaB by cryptolepine in vivo and in vitro. This indicates that cryptolepine may exhibit its anti-inflammatory action by blocking DNA binding of activated NF-kappaB and thus transcription of NF-kappaB-regulated proinflammatory proteins.