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

Abstract

Michellamines A 6 (1) and A 7 (2) are the first dimers of 5,8 0 -coupled naphthylisoquinoline alkaloids with cisconfigured stereocenters in both tetrahydroisoquinoline subunits. They were isolated from the leaves of a recently discovered, yet unidentified Congolese Ancistrocladus liana that shares some morphological characteristics with Ancistrocladus likoko. Two further new dimeric analogs, michellamines B 4 (3) and B 5(4), were obtained, along with two previously likewise unknown monomers, ancistrobonsolines A 1 (5) and A 2 (6), which, besides one single known other example, are the only naphthyldihydroisoquinolines with an M-configured biaryl axis and R-configuration at C-3. Moreover, five compounds earlier reported from other Ancistrocladus species were identified, ancistroealaine C (7), korupensamines A (8a) and B (8b), and michellamines A 2 (9) and E (10). Their complete structural elucidation succeeded due to the fruitful interplay of spectroscopic, chemical, and chiroptical methods. Chemotaxonomically, the stereostructures of the metabolites clearly delineate this Congolese Ancistrocladus liana from all known related species, showing that it might be a new taxon. Ancistrobonsolines A 1 (5) and A 2 (6) exhibited strong preferential cytotoxicities against human PANC-1 pancreatic cancer cells under nutrient-deprived conditions, without displaying toxicity in normal, nutrient-rich medium. Against cervical HeLa cancer cells, the dimeric alkaloids michellamines A 6 (1) and E (10) displayed the highest cytotoxic activities, comparable to that of the standard agent, 5-fluorouracil. Furthermore, ancistrobonsolines A 1 (5) and A 2 (6) showed weak-to-moderate antiprotozoal activities.

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

“…The metabolite proles of most of the Ancistrocladus plants from the Northwestern Congo Basin are likewise dominated by the presence of such hybrid-type alkaloids. [4][5][6][7][14][15][16][17][18][28][29][30] Asian and East African Ancistrocladaceae plants, by contrast, exclusively produce 3S-congured and 6-oxygenated compounds (known as 'Ancistrocladaceae-type' alkaloids), [22][23][24][25] whereas the only other plant family that likewise contains naphthylisoquinolines, the West African Dioncophyllaceae, solely forms alkaloids with R-conguration at C-3, always lacking an oxygen function at C-6 (hence categorized as 'Dioncophyllaceae-type' alkaloids). 24,25 Remarkably, from some of the species endemic to the Southern, Central, and Eastern Congo, metabolites exclusively belonging to the subclass of Ancistrocladaceae-type naphthylisoquinoline alkaloids were isolated, [9][10][11] whereas other species from these regions mainly produce Dioncophyllaceae-type compounds, along with a certain number of Ancistrocladaceae-and hybridtype alkaloids.…”

“…[1][2][3] Comprehensive data about the natural diversity of the genus Ancistrocladus within the Congo region, however, are still lacking. 1,3 Recent eld trips in combination with phylogenetic and phytochemical investigations clearly suggested the presence of further, hitherto unrecognized taxa, [3][4][5][6][7][8][9][10][11] along with the four botanically acknowledged Ancistrocladus species, 1,2,12,13 A. congolensis J. Léonard, A. likoko J. Léonard, A. ealaensis J. Léonard, and A. ileboensis Heubl, Mudogo & G. Bringmann. The latter species was discovered in the Southern Congo Basin, and described for the rst time in 2010, 12 whereas the three other Congolese taxa were botanically acknowledged for the rst time in 1949.…”

“…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,…”

“…[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. 7,9,17,19,21 Structurally most fascinating are the highly unsymmetric mbandakamine-type dimers like e.g., mbandakamines A (1) 4,16 and B 2 (2) 6 ( Fig. 1), which were discovered in a botanically as yet undescribed liana growing in the rainforests near the town of Mbandaka in the Northwestern part of the Democratic Republic of the Congo.…”