Jozimine A₂: The First Dimeric Dioncophyllaceae‐Type Naphthylisoquinoline Alkaloid, with Three Chiral Axes and High Antiplasmodial Activity

Abstract

A new dimeric naphthylisoquinoline alkaloid, jozimine A(2) (2), was isolated from the root bark of an Ancistrocladus species from the Democratic Republic of Congo. Its absolute stereostructure was determined by chemical, spectroscopic, and chiroptical methods, and confirmed by X-ray crystallography. Jozimine A(2) (2) is one of the as yet very rare naphthylisoquinoline dimers whose central biaryl axis is rotationally hindered. Moreover, it is the first natural dimer of a Dioncophyllaceae-type alkaloid, that is, lacking oxygen functions at C6, and bearing R configurations at C3 in its two isoquinoline portions. Despite this decreased steric hindrance, the outer biaryl axes are chiral, too, so that jozimine A(2) (2) has three consecutive stereogenic axes and, together with the four stereogenic centers, seven elements of chirality and is C(2)-symmetric. The new dimer exhibits excellent, and specific, antiplasmodial activity. To further confirm its stereostructure and for likewise testing the bioactivities of its (unnatural) atropo-diastereomer, compound 2 was prepared by semi-synthesis from the co-occurring (and likewise synthetically available) dioncophylline A (5), along with its atropo-diastereomer, 3'-epi-2.

Antiplasmodial Ealapasamines A-C,‘Mixed’ Naphthylisoquinoline Dimers from the Central African Liana Ancistrocladus ealaensis

“…am. P. falciparum NF54/K1L6 cells (cyto-toxicity)Selectivity index to NF54/K1Standard0.007 [1] 3.56 [2] 0.43 [3] 0.008 [4] : NF540.041 [5] n.d.0.364 [4] : K1 1 16.3374.04>1000.41861.291470.452136 2 5.45—>100.210>12.73>610.138>93 3 1.87—>100.034 (NF54)5.98174 0.006 (K1) 997 Jozimine A 2 16 ———0.00115.9114000.016*—

Also the cytotoxicities against rat skeletal myoblasts (L6 cells) were determined (IC 50 in µM). The profile of the dimeric naphthylisoquinoline alkaloid jozimine A 2 16 is used for comparison of the antiplasmodial activities. [1] Melarsoprol.

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“…The profile of the dimeric naphthylisoquinoline alkaloid jozimine A 2 16 is used for comparison of the antiplasmodial activities. [1] Melarsoprol.…”

Michellamines A6 and A7, and further mono- and dimeric naphthylisoquinoline alkaloids from a Congolese Ancistrocladus liana and their antiausterity activities against pancreatic cancer cells

“…6 The latter is known to produce a drastically different metabolic pattern, including dimers with unsymmetric, 6 0 ,1 00 -coupled central axes, 17 with additional oxygen bridges 18 and/or acetal linkages, 21 but so far no symmetric, 6 0 ,6 00 -coupled ones, not even in traces.…”

“…Owing to the pronounced antiprotozoal activities of some naphthylisoquinoline alkaloids, 1,19,[21][22][23] the two new monomers ancistrobonsolines A 1 (5) and A 2 (6) were tested against the pathogens causing malaria (Plasmodium falciparum), human African sleeping sickness (Trypanosoma brucei rhodesiense), Chagas' disease (T. cruzi), and visceral leishmaniosis (Leishmania donovani). The other isolated new dimeric metabolites were not evaluated, since their analogs had previously been found inactive.…”

“…The resulting total crude residue was submitted to a cation-exchange column (Amberlyst-15 from Fluka, Ø 3 cm) to remove undesired, nonbasic metabolites. 21 The obtained alkaloid-enriched fraction was partitioned between water and dichloromethane, giving, aer evaporation, 800 mg of an aqueous subfraction and 30 mg of dichloromethane subfraction. The polar subfraction was dissolved in methanol and resolved by preparative HPLC, using the following gradient: A/B: 0 min 10% B; 25 C NMR data, see Table 1.…”