article · Journal of Natural Products
Researchers investigating the Congolese liana Ancistrocladus ileboensis have isolated and characterised several new and known naphthylisoquinoline alkaloids. Among the newly identified natural products are dioncophylline F, which represents the first 5,8'-coupled alkaloid of its structural class, alongside dioncophyllines C2 and D2 and ancistrocladisine B. The structure and stereochemistry of dioncophylline F were confirmed through total chemical synthesis. Testing against disease models revealed notable bioactivity across multiple isolated compounds. Several identified alkaloids, notably dioncophylline A, demonstrated potent cytotoxic effects against multiple myeloma cells, outperforming the standard drug melphalan. They also showed efficacy against drug-sensitive and multidrug-resistant acute lymphoblastic leukaemia cell lines. In addition, dioncophyllines F, D2, and 5'-O-methyldioncophylline D displayed high and specific inhibitory activity against the malaria parasite Plasmodium falciparum.
Drug resistance poses a severe challenge in both oncology and the treatment of malaria. Discovering unique natural chemical structures from understudied botanical species provides potential starting points for new medicines. Demonstrating that certain plant-derived compounds can kill multidrug-resistant cancer cells more effectively than established therapies, while also inhibiting the malaria parasite, highlights the continued importance of natural product chemistry in addressing difficult medical targets.
This work is at an early research stage, providing preclinical molecular structures and laboratory bioactivity profiles rather than finished therapies. The findings could serve pharmaceutical companies, medicinal chemists, and drug discovery programmes seeking lead candidates for antimalarial formulations or oncology therapeutics targeting multiple myeloma and drug-resistant leukaemia. Significant additional chemical optimisation, toxicology testing, and clinical development would be necessary before any real-world pharmaceutical application is possible.
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Dioncophylline F (1), the first 5,8'-coupled dioncophyllaceous alkaloid (i.e., lacking an oxygen function at C-6 and possessing an R-configuration at C-3), was isolated from the recently described Congolese liana Ancistrocladus ileboensis. Two further, likewise Dioncophyllaceae-type, alkaloids, the dioncophyllines C<sub>2</sub> (2) and D<sub>2</sub> (3), were identified, along with the Ancistrocladaceae-type compound ancistrocladisine B (4), which is oxygenated at C-6 and S-configured at C-3. The structures of the new compounds were determined by spectroscopic, chemical, and chiroptical methods. The stereostructure of 1 was further confirmed by total synthesis. As a consequence of the lack of a methyl group ortho to their biaryl axes, both dioncophylline F (1) and the 7,8'-coupled dioncophylline D<sub>2</sub> (3) occur as pairs of configurationally semistable and, thus, slowly interconverting atropo-diastereomers, whereas dioncophylline C<sub>2</sub> (2), with its 5,1'-linkage, is configurationally stable at the axis. Eight further known naphthylisoquinolines were isolated from A. ileboensis, among them dioncophylline A (P-10), its 4'-O-demethyl analogue P-11, and 5'-O-methyldioncophylline D (7), which were found to display strong cytotoxic activities against multiple myeloma INA-6 cells (P-10 even stronger than the standard drug melphalan) and against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrug-resistant subline, CEM/ADR5000. Moreover, the dioncophyllines 1, 3, and 7 showed high-and specific-activities against the malaria parasite Plasmodium falciparum.
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DOI: 10.1021/acs.jnatprod.6b00967
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