Biomimetic Synthesis of Rhytidenone A and Mode of Action of Cytotoxic Rhytidenone F. (27th January 2020)

• Record Type: Journal Article
• Authors: Yue, Zongwei; Lam, Hiu C.; Chen, Kaiqi; Siridechakorn, Ittipon; Liu, Yaxi; Pudhom, Khanitha; Lei, Xiaoguang
• Is Part Of: Angewandte Chemie. Volume 132:Number 10(2020)
• Page Start: 4144
• Page End: 4149
• Publication Date: 2020-01-27
• Subjects: Apoptose -- Wirkstoffentwicklung -- Zytotoxizität -- Naturstoffe -- Proteine; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201914257
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: The rhytidenone family comprises spirobisnaphthalene natural products isolated from the mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of rhytidenone A was achieved by a Michael reaction/aldol/lactonization cascade in a single step from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F was investigated. The pulldown assay coupled with mass spectrometry analysis revealed the target protein PA28γ is covalently attached to rhytidenone F at the Cys92 residue. The interactions of rhytidenone F with PA28γ lead to the accumulation of p53, which is an essential tumor suppressor in humans. Consequently, the Fas‐dependent signaling pathway is activated to initiate cellular apoptosis. These studies have identified the first small‐molecule inhibitor targeting PA28γ, suggesting rhytidenone F may serve as a promising natural product lead for future anticancer drug development. Abstract : Die biomimetische Synthese von Rhytidenon A wurde durch eine Kaskade aus Michael‐Reaktion, Aldolreaktion und Lactonisierung in einem einzigen Schritt aus der postulierten Biosynthesevorstufe Rhytidenon F erreicht. Das hoch zytotoxische Rhytidenon F greift PA28γ an und führt zur Anreicherung des Tumorsuppressors p53. Es ist daher ein vielversprechender Naturstoff für die zukünftige Entwicklung von Krebsmedikamenten.