Ancistrobrevidines A-C and related naphthylisoquinoline alkaloids with cytotoxic activities against HeLa and pancreatic cancer cells, from the liana Ancistrocladus abbreviatus.

From the leaves of Ancistrocladus abbreviatus (Ancistrocladaceae), six 5,1'-coupled naphthyldihydroisoquinoline alkaloids were isolated, ancistrobrevidines A-C (5-7), 5-epi-dioncophyllidine C2 (10), 6-O-methylhamatinine (8), and 6-O-methylancistectorine A3 (9); the two latter compounds were already known from related plants. Most strikingly, this series comprises alkaloids belonging to three different subclasses of naphthylisoquinolines. Ancistrobrevidine C (7) and the alkaloids 8 and 9, displaying the S-configuration at C-3 and an oxygen function at C-6, are three further representatives of the large subgroup of 5,1'-coupled Ancistrocladaceae-type compounds found in nature. 5-epi-Dioncophyllidine C2 (10), lacking an oxygen function at C-6 and having the R-configuration at C-3, is only the third representative of a 5,1'-linked Dioncophyllaceae-type naphthylisoquinoline. Likewise rare are 5,1'-coupled hybrid-type alkaloids, which are 6-oxygenated and 3R-configured. The ancistrobrevidines A (5) and B (6) are the only second and third examples of such 5,1'-linked naphthylisoquinolines in Ancistrocladus species showing the landmarks of both, Ancistrocladaceae- and Dioncophyllaceae-type naphthylisoquinolines. In the roots of A. abbreviatus, two further unprecedented 5,1'-coupled alkaloids were discovered, ancistrobreviquinones A (11) and B (12), consisting of a 3,4-naphthoquinone portion coupled to a tetrahydroisoquinoline subunit. They are the very first quinoid naphthylisoquinolines possessing an ortho-diketone entity. Ancistrobrevidine C (7) exerted pronounced antiproliferative activities against HeLa cervical cancer cells and preferential cytotoxicity towards PANC-1 human pancreatic cancer cells under nutrient-deprived conditions following the antiausterity approach. Moreover, 7 suppressed the migration of PANC-1 cells and significantly inhibited colony formation under nutrient-rich conditions in a concentration-dependent manner, and induced dramatic alteration in cell morphology, leading to cell death.

A Near-Complete Series of Four Atropisomeric Jozimine A2-Type Naphthylisoquinoline Dimers with Antiplasmodial and Cytotoxic Activities and Related Alkaloids from Ancistrocladus abbreviatus.

Three new naphthylisoquinoline dimers, jozibrevines A-C (1a-c), were isolated from the West African shrub Ancistrocladus abbreviatus, along with the known dimer jozimine A2 (1d). The two molecular moieties of 1a-d are coupled via the sterically constrained 3',3″-positions of their two naphthalene units, so that the central biaryl linkage is rotationally hindered. With the two outer axes also being chiral, 1a-d possess three consecutive stereogenic axes. The four isolated dimers all have the same constitutions and identical absolute configurations at the four stereogenic centers, but differ by their axial chirality. They belong to the extremely small class of Dioncophyllaceae-type naphthylisoquinoline dimers, i.e., being devoid of oxygen functions at C-6 and bearing the R-configuration at C-3 in their isoquinoline portions. Besides these dimers, the plant produces predominantly typical Ancistrocladaceae-type monomeric compounds, i.e., with the S-configuration at C-3 and an oxygen function at C-6, such as the new ancistrobrevines K (5) and L (6). Furthermore, a new hybrid-type (i.e., mixed Ancistrocladaceae/Dioncophyllaceae-type) alkaloid was identified, named ancistrobrevine M (7), which is 3R-configured and 6-oxygenated. Remarkable was the discovery of its "inverse hybrid-type" counterpart, dioncoline A (8). It is the as yet only known 3S-configured naphthylisoquinoline lacking an O-functionality at C-6. The new jozibrevines A-C (1a-c) exhibited pronounced antiplasmodial activities in the submicromolar range, with 1a being the most potent compound (IC50, 0.012 µM). Furthermore, jozimine A2 (1d) showed cytotoxicity against human colon carcinoma (HT-29), fibrosarcoma (HT1080), and multiple myeloma (MM.1S) cancer cells, displaying IC50 values of 12.0, 9.0, and 5.0 µM, respectively, whereas jozibrevines A (1a) and B (1b) were nontoxic in this concentration range.

Ancistrobrevinium A, the first N-methylated, cationic naphthylisoquinoline alkaloid, from the tropical liana Ancistrocladus abbreviatus (Ancistrocladaceae).

Ancistrobrevinium A (1) is the first N-methylated and non-hydrogenated, and thus cationic naphthylisoquinoline alkaloid. It was discovered in the root bark extract of the phytochemically productive West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Its constitution was elucidated by HR-ESI-MS and 1D and 2D NMR. Due to the steric hindrance in the proximity of the linkage between the naphthalene and isoquinoline parts, the biaryl axis is rotationally hindered. It thus constitutes a stable element of chirality - the only one in the new alkaloid since, different from most other naphthylisoquinoline alkaloids, it has no stereogenic centers. The axial configuration of 1 was assigned by electronic circular dichroism (ECD) investigations, which gave a positive couplet, indicating a 'positive chirality', here corresponding to a P-configuration. Ancistrobrevinium A (1) showed a weak cytotoxic activity against A549 lung cancer cells (IC50 = 50.6 µM).

Ancistrobrevines E-J and related naphthylisoquinoline alkaloids from the West African liana Ancistrocladus abbreviatus with inhibitory activities against Plasmodium falciparum and PANC-1 human pancreatic cancer cells.

From the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae), ten new naphthylisoquinoline alkaloids (7a, 7b, 8a, 8b, and 9-14), displaying three different coupling types (5,1', 5,8', and 7,8'), were isolated, among them a series of five 5,1'-linked representatives and four metabolites belonging to the rare group of 7,8'-coupled alkaloids. Two of the alkaloids, the ancistrobrevines I (13) and J (14), are only the fourth and fifth examples of 7,8'-linked naphthyldihydroisoquinolines ever found in nature. The stereostructures of the new plant metabolites were determined by spectroscopic, chemical (oxidative degradation), and chiroptical (electronic circular dichroism) methods. For the assignment of the axial configuration of 13 and 14 relative to the stereocenter at C-3, which is too far away for significant NOE long-range interactions, these 7,8'-coupled naphthyldihydroisoquinolines were stereoselectively converted into the respective cis-configured tetrahydroisoquinoline analogs. The newly generated 'auxiliary' stereocenter at C-1 permitted decisive NOE interactions between the isoquinoline and the naphthalene parts, and thus a reliable attribution of the axial configuration of 13 and 14. In addition, five known compounds (3, 5, 16, 17, and 20), previously discovered in related African and Asian Ancistrocladus species, have now for the first time been identified in A. abbreviatus. All of these alkaloids are S-configured at C-3 and bear an oxygen function at C-6, and are, thus, typical Ancistrocladaceae-type compounds. Some of the alkaloids of A. abbreviatus exhibited promising activities against the malaria parasite Plasmodium falciparum and PANC-1 human pancreatic cancer cells.

Habropetaline A, an antimalarial naphthylisoquinoline alkaloid from Triphyophyllum peltatum.

The isolation, structural elucidation, and antiprotozoal activities of habropetaline A, a novel naphthylisoquinoline alkaloid from Triphyophyllum peltatum, are described. This alkaloid had previously only been identified on line, by the LC-MS/MS-NMR-CD triad, in the crude extract of the rare and difficult-to-provide related plant species Habropetalum dawei, whose small quantities available had not permitted to isolate the compound. As predicted by quantitative structure-activity relationship (QSAR) investigations, habropetaline A exhibits strong antimalarial activity against Plasmodium falciparum, while it is inactive against other protozoal pathogens (Trypanosoma brucei rhodesience, T. cruzi, and Leishmania donovani).