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

Abstract

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.

Naphthylisoindolinone alkaloids: the first ring-contracted naphthylisoquinolines, from the tropical liana Ancistrocladus abbreviatus, with cytotoxic activity

“…[5][6][7][8][9] From this tropical plant, no less than 69 such compounds have so far been isolated, many of them with unique molecular scaffolds. 5,[10][11][12][13][14][15][16][17][18] With 33 examples, 5,10,11,13,14,17 naphthyltetrahydroisoquinoline alkaloids such as ancistrobrevine A (1), its 6-O-demethyl analogue 2, 5,14 and ancistrobrevine D (3) 5,13 (Fig. 1) constitute the major portion of compounds produced by the plant.…”

“…17 Likewise isolated were quinoid structures like ancistrobreviquinone A (10), 15 possessing an ortho-naphthoquinone entity. Even more remarkable is the structure of the rst 1-demethylated naphthylisoquinoline alkaloid, 1-nor-8-O-demethylancistro-brevine H (12), 18 lacking the otherwise generally present methyl group at C-1. This compound was isolated along with a series of unprecedented seco-alkaloids from the roots of A. abbreviatus, 18 having undergone a cleavage of the heterocyclic ring, with an elimination of the entire C-1/Me-1 unit, among them ancistrosecoline D (13) (Fig.…”

“…This alkaloid exerted potent, and selective, cytotoxicity against HeLa cervical cancer cells by inducing apoptosis. 18 The 'chemical creativity' of A. abbreviatus is even larger, as shown in this report by the discovery of a series of metabolites constituting a novel subtype of axially chiral naphthylisoindolinone alkaloids, named ancistrobrevolines A-D (14)(15)(16)(17). In these compounds, the six-membered heterocyclic part of the isoquinoline portion has undergone a ring contraction to give a ve-membered heterocycle as part of an isoindolinone system, with loss of the whole C-3/Me-3 entity, which had so far been present in all other naphthylisoquinoline alkaloids.…”

pysisyphus: Exploring potential energy surfaces in ground and excited states

“…The biaryl motif plays a key role in many pharmaceutical compounds, [140] such as antihypertensive sartans [141] and nonsteroidal antiinflammatory drugs, [142,143] and also in natural products [144] such as cannabinol [145] and many alkaloids. [146][147][148] Selective cross-coupling of aryl-residues is often achieved by using transition metal catalysts. [149][150][151][152][153][154][155][156] As transition metal catalysts are often toxic and expensive, metal-free aryl cross-coupling reactions have also been proposed.…”

Organocatalyzed Cascade Aza-Michael/Aldol Reaction for Atroposelective Construction of 4-Naphthylquinoline-3-carbaldehydes

“…It is well-known that the axial chirality, which generates from hindered rotation about a single bond, is a subtype of chirality . Axially chiral binaphthyls are widely found in many natural products, bioactive molecules, as well as optical materials . Furthermore, they are also used as ligands and catalysts in asymmetric transformations .…”