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.

中文翻译：

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仿制的吡啶酮A的合成和细胞毒性吡啶酮F的作用方式。

Rhytidenone家族包含从红树林内生真菌Rhytidhysteron rufulum AS21B分离出的螺双萘天然产物。拟南酮A的仿生合成是通过迈克尔反应/醛醇缩合/内酯化步骤从所提出的生物合成前体Rhytidenone F一步完成的。此外，还研究了具有高度细胞毒性的Rhytidenone F的作用方式。下拉分析与质谱分析相结合显示，目标蛋白PA28γ在Cys92残基处共价附于RhytidenoneF。吡啶酮F与PA28γ的相互作用导致p53的积累，而p53是人类必需的肿瘤抑制因子。因此，依赖于Fas的信号通路被激活以启动细胞凋亡。