Ancistrosecolines A–F, Unprecedented seco-Naphthylisoquinoline Alkaloids from the Roots of Ancistrocladus abbreviatus, with Apoptosis-Inducing Potential against HeLa Cancer Cells

Ancistrosecolines A–F ( 8 – 13 ) are the first seco -type naphthylisoquinoline alkaloids discovered in Nature. In all these novel compounds, the tetrahydroisoquinoline ring is cleaved, with loss of C-1. They were isolated from the root bark of Ancistrocladus abbreviatus (Ancistrocladaceae), along with 1- nor -8- O -demethylancistrobrevine H ( 14 ), which is the first naturally occurring naphthylisoquinoline lacking the otherwise generally present methyl group at C-1. The stereostructures of the new alkaloids were established by HRESIMS, 1D and 2D NMR, oxidative degradation, and experimental and quantum-chemical ECD investigations. Ancistrosecolines A–F ( 8 – 13 ) and 1- nor -8- O -demethylancistrobrevine H ( 14 ) are typical Ancistrocladaceae-type metabolites, i.e., oxygenated at C-6 and S -configured at C-3, belonging to the subclasses of 7,1′- and 7,8′-coupled alkaloids. The biaryl linkages of 8 – 14 are rotationally hindered due to bulky ortho -substituents next to the axes. Owing to the constitutionally unsymmetric substitution patterns on each side of the axis, this C–C single bond represents an element of chirality in 1- nor -8- O -demethylancistrobrevine H ( 14 ) and in ancistrosecolines A–D ( 8 – 11 ). In ancistrosecolines E ( 12 ) and F ( 13 ), however, the likewise rotationally hindered biaryl axes do not constitute chiral elements, due to a symmetric substitution pattern, with its identical two methoxy functions at C-6 and C-8 in the phenyl subunit. And these two methoxy groups are, for the first time, not constitutionally heterotopic, but diastereotopic to each other. Ancistrosecoline D ( 11 ) exhibits strong cytotoxicity against HeLa cervical cancer cells. As visualized by Hoechst nuclei staining and by real-time imaging experiments, 11 induced massive nuclei fragmentation in HeLa cells, leading to apoptotic cell death.