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

Three new naphthylisoquinoline dimers, jozibrevines A-C (-), were isolated from the West African shrub , along with the known dimer jozimine A (). The two molecular moieties of - 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, - 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 -configuration at C-3 in their isoquinoline portions. Besides these dimers, the plant produces predominantly typical Ancistrocladaceae-type monomeric compounds, i.e., with the -configuration at C-3 and an oxygen function at C-6, such as the new ancistrobrevines K () and L (). Furthermore, a new hybrid-type (i.e., mixed Ancistrocladaceae/Dioncophyllaceae-type) alkaloid was identified, named ancistrobrevine M (), which is 3-configured and 6-oxygenated. Remarkable was the discovery of its "inverse hybrid-type" counterpart, dioncoline A (). It is the as yet only known 3-configured naphthylisoquinoline lacking an -functionality at C-6. The new jozibrevines A-C (-) exhibited pronounced antiplasmodial activities in the submicromolar range, with being the most potent compound (IC, 0.012 μM). Furthermore, jozimine A () showed cytotoxicity against human colon carcinoma (HT-29), fibrosarcoma (HT1080), and multiple myeloma (MM.1S) cancer cells, displaying IC values of 12.0, 9.0, and 5.0 μM, respectively, whereas jozibrevines A () and B () were nontoxic in this concentration range.