article · Journal of Natural Products
Two previously unknown naphthylisoquinoline dimers, named jozilebomines A and B, have been isolated alongside the known compound jozimine A2 from the roots of Ancistrocladus ileboensis, a liana native to the Democratic Republic of the Congo. These compounds feature unusual unsymmetric binaphthalene couplings and three consecutive chiral axes. Laboratory tests revealed that the isolated dimers possess distinct antiplasmodial properties and potent cytotoxic effects against HeLa human cervical cancer cells. Under nutrient-deprived conditions, the dimers demonstrated preferential cytotoxicity against PANC-1 human pancreatic cancer cells. Brief exposure to non-cytotoxic concentrations of the compounds also significantly inhibited the ability of these pancreatic cancer cells to form colonies. These results indicate that jozilebomines A and B, along with jozimine A2, could serve as chemical starting points for developing therapies aimed at targeting pancreatic cancer.
Pancreatic cancer cells frequently survive in nutrient-starved environments within tumours, making them difficult to treat with standard therapies. Compounds showing antiausterity activity selectively target cancer cells under starvation conditions without harming healthy cells in normal environments. Identifying plant-derived natural products with this specific activity provides molecular templates that could assist in addressing challenging cancers that resist conventional medical treatments.
These findings identify early-stage chemical candidates for oncology drug discovery programmes focusing on pancreatic and cervical cancers, as well as malaria therapeutics. Potential users include medicinal chemists, pharmaceutical companies, and cancer research teams working on antiausterity mechanisms. Because the work remains at the stage of laboratory isolation and in vitro cell culture testing, any commercialised therapeutic product would require extensive preclinical optimisation, safety profiling, and clinical trials.
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Two new naphthylisoquinoline dimers, jozilebomines A (1a) and B (1b), were isolated from the roots of the Congolese plant Ancistrocladus ileboensis, along with the known dimer jozimine A<sub>2</sub> (2). These compounds are Dioncophyllaceae-type metabolites, i.e., lacking oxygen functions at C-6 and with an R-configuration at C-3 in their tetrahydroisoquinoline moieties. The dimers 1a and 1b consist of two 7,1'-coupled naphthylisoquinoline monomers linked through an unprecedented 3',6″-coupling in the binaphthalene core and not, as in 2, via the C-3-positions of the two naphthalene units. Thus, different from the C<sub>2</sub>-symmetric jozimine A<sub>2</sub> (2), the new jozilebomines are constitutionally unsymmetric. The central biaryl axis of each of the three dimers is rotationally hindered, so that 1a, 1b, and 2 possess three consecutive chiral axes. The two jozilebomines have identical constitutions and the same absolute configurations at all four stereogenic centers, but differ from each other in their axial chirality. Their structural elucidation was achieved by HRESIMS, 1D and 2D NMR, oxidative degradation, and experimental and calculated ECD data. They exhibited distinct and specific antiplasmodial activities. All dimers showed potent cytotoxicity against HeLa human cervical cancer cells and preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions. Furthermore, these dimers significantly inhibited the colony formation of PANC-1 cells, even when exposed to noncytotoxic concentration for a short time. Jozilebomines A (1a) and B (1b) and jozimine A<sub>2</sub> (2) represent novel potential candidates for future drug development against pancreatic cancer.
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DOI: 10.1021/acs.jnatprod.7b00650
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