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

Abstract

Three unusual heterodimeric naphthylisoquinoline alkaloids, named ealapasamines A-C (1–3), were isolated from the leaves of the tropical plant Ancistrocladus ealaensis J. Léonard. These ‘mixed’, constitutionally unsymmetric dimers are the first stereochemically fully assigned cross-coupling products of a 5,8′- and a 7,8′-coupled naphthylisoquinoline linked via C-6′ in both naphthalene portions. So far, only two other West and Central Ancistrocladus species were known to produce dimers with a central 6,6″-axis, yet, in contrast to the ealapasamines, usually consisting of two 5,8′-coupled monomers, like e.g., in michellamine B. The new dimers 1–3 contain six elements of chirality, four stereogenic centers and the two outer axes, while the central biaryl axis is configurationally unstable. The elucidation of the complete stereostructures of the ealapasamines was achieved by the interplay of spectroscopic methods including HRESIMS, 1D and 2D NMR (in particular ROESY measurements), in combination with chemical (oxidative degradation) and chiroptical (electronic circular dichroism) investigations. The ealapasamines A-C display high antiplasmodial activities with excellent half-maximum inhibition concentration values in the low nanomolar range.

Biomimetic Total Synthesis of Mbandakamine A and Further Antiplasmodial Naphthylisoquinoline Dimers

“…In view of the promising anti‐infective activities of some dimeric naphthylisoquinolines,,, the new products were tested against the protozoan parasites causing malaria, African sleeping sickness, and leishmaniasis. Most remarkable was the excellent antiplasmodial activity of 17 against the chloroquine‐resistant K1 strain of Plasmodium falciparum in vitro (IC 50 =0.003 μ M), combined with a very low cytotoxicity (IC 50 =62.26 μ M), making a selectivity index of more than 20,000 – better than any mono‐ or dimeric naphthylisoquinolines ever tested ,…”

“…The formation of the other regioisomeric coupling products 17 , 18 a and 18 b , and 19 a – with their novel molecular frameworks – is most useful for our ongoing structure‐activity relationship investigations on the anti‐infective properties of such quateraryl compounds,,, and for the directed search for these potential natural products in the plants, which is now facilitated by the availability of synthetic reference material. This work is in progress.…”

“…Depending on their individual structures, they have pronounced anti‐infective or antitumoral activities ,. More than 200 representatives of this unique class of natural products have so far been isolated, among them more than 20 dimers, which possess even three biaryl axes ,. A structurally most fascinating dimer is mbandakamine A ( 1 a ) (see Figure ), which has recently been isolated, along with its M ‐configured atropo‐diastereomer mbandakamine B ( 1 b ), from the leaves of a botanically as yet undescribed Ancistrocladus species growing in the proximity of the town of Mbandaka in the Democratic Republic of the Congo .…”

Antiprotozoal dimeric naphthylisoquinolines, mbandakamines B3 and B4, and related 5,8′-coupled monomeric alkaloids, ikelacongolines A–D, from a Congolese Ancistrocladus liana

“…It is all the more remarkable that phytochemical investigations on Central African Ancistrocladus plants have picked up speed only quite recently, during the past decade, [4][5][6][7][8][9][10][11][14][15][16][17][18][19][20][21] considering that intense isolation work on Asian as well as West and East African taxa had started much earlier, leading to the discovery of structurally unique mono-and dimeric naphthylisoquinoline alkaloids with promising antiparasitic and antiviral activities. [22][23][24][25][26][27] More recent phytochemical studies on Ancistrocladus lianas from the Congo region, including all of the four valid taxa [14][15][16][17][18][19][20][21] mentioned above, but also botanically as yet unidentied plants, [4][5][6][7][8][9][10][11] furnished a whole series of further novel-type naphthylisoquinoline alkaloids, among them N,Ccoupled compounds 9,10 and, in particular, dimeric representatives with complex molecular architectures. [4][5][6]…”

“…[22][23][24][25][26][27] More recent phytochemical studies on Ancistrocladus lianas from the Congo region, including all of the four valid taxa [14][15][16][17][18][19][20][21] mentioned above, but also botanically as yet unidentied plants, [4][5][6][7][8][9][10][11] furnished a whole series of further novel-type naphthylisoquinoline alkaloids, among them N,Ccoupled compounds 9,10 and, in particular, dimeric representatives with complex molecular architectures. [4][5][6][7][8][14][15][16]18,21 Some of these secondary metabolites attracted attention due to their extraordinary antiplasmodial 6,8,15,16 or antileishmanial 10 activities or, according to their individual structures, to their strong antiproliferative effects against human leukemia, 16,18,20 cervical HeLa, 7,21 or pancreatic cancer cells. 7,9,…”