Zongwei Yue, Hiu C. Lam, Kaiqi Chen, Ittipon Siridechakorn, Yaxi Liu, Khanitha Pudhom,
Xiaoguang Lei*
Angew. Chem. Int. Ed. doi: 10.1002/anie.201914257
Rhytidenones family are spirobisnaphthalene natural products isolated from mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of complex rhytidenone A was achieved via a sequence of Michael reaction, aldol and lactonization cascade in a single step, from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F has been 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 would lead to the accumulation of p53 which is an essential tumor suppressor in humans. Consequently, the Fas‐dependent signalling pathway will be activated to initiate cellular apoptosis. Our 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.
Rhytidenones family are spirobisnaphthalene natural products isolated from mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of complex rhytidenone A was achieved via a sequence of Michael reaction, aldol and lactonization cascade in a single step, from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F has been 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 would lead to the accumulation of p53 which is an essential tumor suppressor in humans. Consequently, the Fas‐dependent signalling pathway will be activated to initiate cellular apoptosis. Our 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.