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

Journal of Natural Products
2020.0

Abstract

Ancistrosecolines A-F (<b>8</b>-<b>13</b>) are the first <i>seco</i>-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 <i>Ancistrocladus abbreviatus</i> (Ancistrocladaceae), along with 1-<i>nor</i>-8-<i>O</i>-demethylancistrobrevine H (<b>14</b>), 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 (<b>8</b>-<b>13</b>) and 1-<i>nor</i>-8-<i>O</i>-demethylancistrobrevine H (<b>14</b>) are typical Ancistrocladaceae-type metabolites, i.e., oxygenated at C-6 and <i>S</i>-configured at C-3, belonging to the subclasses of 7,1'- and 7,8'-coupled alkaloids. The biaryl linkages of <b>8</b>-<b>14</b> are rotationally hindered due to bulky <i>ortho</i>-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-<i>nor</i>-8-<i>O</i>-demethylancistrobrevine H (<b>14</b>) and in ancistrosecolines A-D (<b>8</b>-<b>11</b>). In ancistrosecolines E (<b>12</b>) and F (<b>13</b>), 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 (<b>11</b>) exhibits strong cytotoxicity against HeLa cervical cancer cells. As visualized by Hoechst nuclei staining and by real-time imaging experiments, <b>11</b> induced massive nuclei fragmentation in HeLa cells, leading to apoptotic cell death.

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