article · Journal of Natural Products
Chemical investigation of the Congolese liana Ancistrocladus ealaensis has yielded several new dimeric naphthylisoquinoline alkaloids, designated michellamine A5 and mbandakamines C to E, alongside the known dimer mbandakamine A. These compounds consist of constitutionally unsymmetric dimers formed by 5,8'-coupled monomers. While michellamine A5 features a configurationally unstable central axis linking the least-hindered positions, the mbandakamines possess three consecutive stereogenic axes linked via an unprecedented 6',1"-coupling that creates significant steric crowding. The study also identified four new monomeric naphthylisoquinolines, termed ancistroealaines C to F, and four related isoquinolines devoid of naphthalene moieties, termed ealaines A to D. Biological evaluation revealed that mbandakamines C and D possess strong activity against the malaria parasite Plasmodium falciparum, as well as potent cytotoxic effects against human leukaemia cells and drug-resistant tumour cell lines.
Drug-resistant strains of malaria and cancer pose critical challenges to global public health. Finding structurally complex natural products from African plant species provides new chemical templates for medicinal chemistry. Understanding the unique architecture and potent biological action of these alkaloids helps researchers investigate alternative therapeutic mechanisms to overcome existing drug resistances.
This work represents early-stage natural product discovery. The demonstrated cytotoxic and antiparasitic potencies make mbandakamines C and D potential lead candidates for pharmaceutical developers targeting malaria and resistant leukaemias. Significant preclinical research, including synthetic pathway development, toxicity screening, and in vivo efficacy testing, is required before any commercial or clinical application can be pursued.
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Four new dimeric naphthylisoquinoline alkaloids, michellamine A<sub>5</sub> (2) and mbandakamines C-E (4-6), were isolated from the Congolese plant Ancistrocladus ealaensis, along with the known dimer mbandakamine A (3). They represent constitutionally unsymmetric dimers, each consisting of two 5,8'-coupled naphthylisoquinoline monomers. While the molecular halves of michellamine A<sub>5</sub> (2) are linked via C-6' of both of the naphthalene moieties, i.e., via the least-hindered positions, so that the central biaryl axis is configurationally unstable and not an additional element of chirality, the mbandakamines 3-6 possess three consecutive stereogenic axes. Their monomeric units are linked through an unprecedented 6',1″-coupling in the binaphthalene core, leading to a high steric load, since the central axis is located in one of the peri-positions, neighboring one of the outer axes. In addition, four new 5,8'-coupled monomeric naphthylisoquinolines, viz., ancistroealaines C-F (7-10), were identified, along with four "naphthalene-devoid" tetra- and dihydroisoquinolines, named ealaines A-D (11-14). The new mbandakamines C (4) and D (5) showed pronounced activities against the malaria parasite Plasmodium falciparum, and they were likewise found to display strong cytotoxic activities against human leukemia (CCRF-CEM) and multi-drug-resistant tumor cells (CEM/ADR5000).
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DOI: 10.1021/acs.jnatprod.7b01041
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