Structural variety and pharmacological potential of naphthylisoquinoline alkaloids.

Naphthylisoquinoline alkaloids are a fascinating class of natural biaryl compounds. They show characteristic mono- and dimeric scaffolds, with chiral axes and stereogenic centers. Since the appearance of the last comprehensive overview on these secondary plant metabolites in this series in 1995, the number of discovered representatives has tremendously increased to more than 280 examples known today.

Cytotoxicity of dioncophylline A and related naphthylisoquinolines in leukemia cells, mediated by NF-κB inhibition, angiogenesis suppression, G2/M cell cycle arrest, and autophagy induction.

Background: Inhibition of NF-κB activity represents a strategy to treat acute myeloid leukemia, one of the most lethal leukemia types. Naphthylisoquinolines (NIQs) are cytotoxic alkaloids from lianas of the families Ancistrocladaceae and Dioncophyllaceae, which are indigenous to tropical rainforests.

Purpose: Uncovering therapeutic possibilities and underlying molecular mechanisms of dioncophylline A and its derivatives towards NF-κB related cellular processes.

Ancistrocladinium A Induces Apoptosis in Proteasome Inhibitor-Resistant Multiple Myeloma Cells: A Promising Therapeutic Agent Candidate.

The ,-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress.

Molecular determinants of the response of cancer cells towards geldanamycin and its derivatives.

Geldanamycin is an ansamycin-derivative of a benzoquinone isolated from Streptomyces hygroscopicus. It inhibits tyrosine kinases and heat shock protein 90 (HSP90). Geldanamycin and 11 derivatives were subjected to molecular docking to HSP90, and 17-desmethoxy-17-N,N-dimethylamino-geldanamycin (17-DMAG) was the compound with the highest binding affinity (-7.

Ancistrobrevinium A, the first -methylated, cationic naphthylisoquinoline alkaloid, from the tropical liana (Ancistrocladaceae).

Ancistrobrevinium A () is the first -methylated and non-hydrogenated, and thus cationic naphthylisoquinoline alkaloid. It was discovered in the root bark extract of the phytochemically productive West African liana (Ancistrocladaceae). Its constitution was elucidated by HR-ESI-MS and 1D and 2D NMR.

Jozibrevine D from Ancistrocladus ileboensis, the fifth alkaloid in a series of six possible atropo-diastereomeric naphthylisoquinoline dimers, showing antiparasitic and antileukemic activities.

A new dimeric naphthylisoquinoline alkaloid, jozibrevine D (4e), was isolated from the Central-African liana Ancistrocladus ileboensis. It is a Dioncophyllaceae-type metabolite, being R-configured at C-3 and lacking an oxygen function at C-6 in both isoquinoline moieties. The two identical monomers of jozibrevine D are symmetrically linked via the sterically constrained 3',3''-positions of the naphthalene units so that the central biaryl linkage is rotationally hindered and the alkaloid is, thus, C-symmetric.

Dioncophyllidine E: The first configurationally semi-stable, 7,3'-coupled naphthyldihydroisoquinoline alkaloid, from Ancistrocladus abbreviatus, with antiausterity activity against PANC-1 human pancreatic cancer cells.

The discovery of a new naphthylisoquinoline alkaloid, dioncophyllidine E (4), from the tropical liana Ancistrocladus abbreviatus (Ancistrocladaceae) is described. Due to its rare 7,3'-coupling type, combined with the lack of an oxygen function at C-6, it is configurationally semi-stable at the biaryl axis, and thus occurs as a pair of slowly interconverting atropo-diastereomers, 4a and 4b. Its constitution was assigned mainly by 1D and 2D NMR.

Asian Ancistrocladus Lianas as Creative Producers of Naphthylisoquinoline Alkaloids.

This book describes a unique class of secondary metabolites, the mono- and dimeric naphthylisoquinoline alkaloids. They occur in lianas of the paleotropical Ancistrocladaceae and Dioncophyllaceae families, exclusively. Their unprecedented structures include stereogenic centers and rotationally hindered, and thus likewise stereogenic, axes.

Correction: Naphthylisoindolinone alkaloids: the first ring-contracted naphthylisoquinolines, from the tropical liana , with cytotoxic activity.

[This corrects the article DOI: 10.1039/D2RA05758A.].

Naphthylisoindolinone alkaloids: the first ring-contracted naphthylisoquinolines, from the tropical liana , with cytotoxic activity.

The West African liana is a rich source of structurally most diverse naphthylisoquinoline alkaloids. From its roots, a series of four novel representatives, named ancistrobrevolines A-D (14-17) have now been isolated, displaying an unprecedented heterocyclic ring system, where the usual isoquinoline entity is replaced by a ring-contracted isoindolinone part. Their constitutions were elucidated by 1D and 2D NMR and HR-ESI-MS.

The Stereoselective Total Synthesis of Axially Chiral Naphthylisoquinoline Alkaloids.

The naphthylisoquinoline (NIQ) alkaloids are a thrilling class of natural biaryls─structurally, biosynthetically, and pharmacologically. A common feature of these metabolites is the biaryl bond between their naphthalene and isoquinoline moieties, which in most cases is rotationally hindered, leading to the phenomenon of axial chirality. Depending on their individual structures, including the respective axial configurations, NIQs show promising bioactivities.

Spirombandakamine A and Cyclombandakamines A and A, Polycyclic Naphthylisoquinoline Dimers, with Antiprotozoal Activity, from a Congolese Plant.

Spirombandakamine A () is only the third known naphthylisoquinoline dimer with a spiro-fused novel molecular framework and the first such representative to possess a relative -configuration at the two chiral centers in both tetrahydroisoquinoline subunits. It was found in the leaves of a botanically as yet unidentified Congolese plant, which is morphologically closely related to the Central African taxon . Likewise isolated were the new cyclombandakamines A () and A (), which belong to another most recently discovered type of unusual oxygen-bridged naphthylisoquinoline dimers and two previously described "open-chain" analogues, mbandakamines C () and D ().

Ancistrobrevidines A-C and related naphthylisoquinoline alkaloids with cytotoxic activities against HeLa and pancreatic cancer cells, from the liana Ancistrocladus abbreviatus.

From the leaves of Ancistrocladus abbreviatus (Ancistrocladaceae), six 5,1'-coupled naphthyldihydroisoquinoline alkaloids were isolated, ancistrobrevidines A-C (5-7), 5-epi-dioncophyllidine C (10), 6-O-methylhamatinine (8), and 6-O-methylancistectorine A (9); the two latter compounds were already known from related plants. Most strikingly, this series comprises alkaloids belonging to three different subclasses of naphthylisoquinolines. Ancistrobrevidine C (7) and the alkaloids 8 and 9, displaying the S-configuration at C-3 and an oxygen function at C-6, are three further representatives of the large subgroup of 5,1'-coupled Ancistrocladaceae-type compounds found in nature.

Naphthylisoquinoline alkaloids and their synthetic analogs as potent novel inhibitors against Babesia canis in vitro.

Babesia canis is the predominant and clinically relevant canine Babesia species in Europe. Transmitted by vector ticks, the parasite enters red blood cells and induces a severe, potentially fatal hemolytic anemia. Here, we report on the antibabesial activities of three extracts of the West African tropical plant species Triphyophyllum peltatum (Dioncophyllaceae) and Ancistrocladus abbreviatus (Ancistrocladaceae) and of 13 genuine naphthylisoquinoline alkaloids isolated thereof.

Ancistrosecolines A-F, Unprecedented -Naphthylisoquinoline Alkaloids from the Roots of , with Apoptosis-Inducing Potential against HeLa Cancer Cells.

Ancistrosecolines A-F (-) are the first -type naphthylisoquinoline alkaloids discovered in Nature. In all these novel compounds, the tetrahydroisoquinoline ring is cleaved, with loss of C-1. They were isolated from the root bark of (Ancistrocladaceae), along with 1--8--demethylancistrobrevine H (), which is the first naturally occurring naphthylisoquinoline lacking the otherwise generally present methyl group at C-1.

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.

Ealamines A-H, a Series of Naphthylisoquinolines with the Rare 7,8'-Coupling Site, from the Congolese Liana , Targeting Pancreatic Cancer Cells.

From the twigs and leaves of the Central African liana (Ancistrocladaceae), a series of ten 7,8'-coupled naphthylisoquinoline alkaloids were isolated, comprising eight new compounds, named ealamines A-H (, , -), and two known ones, 6--demethylancistrobrevine A () and yaoundamine A (), which had previously been found in related African species. Only one of the new compounds within this series, ealamine H (), is a typical Ancistrocladaceae-type alkaloid, with 3-configuration at C-3 and an oxygen function at C-6, whereas seven of the new alkaloids are the first 7,8'-linked "hybrid-type" naphthylisoquinoline alkaloids, i.e.

An Unusually Broad Series of Seven Cyclombandakamines, Bridged Dimeric Naphthylisoquinoline Alkaloids from the Congolese Liana Ancistrocladus ealaensis.

A series of seven unusual dimeric naphthylisoquinoline alkaloids was isolated from the leaves of the tropical liana Ancistrocladus ealaensis J. Léonard, named cyclombandakamine A (1), 1-epi-cyclombandakamine A (2), and cyclombandakamines A (3-7). These alkaloids have a chemically thrilling structural array consisting of a twisted dihydrofuran-cyclohexenone-isochromene system.

Dimeric naphthylisoquinoline alkaloids: polyketide-derived axially chiral bioactive quateraryls.

Covering: up to April 2019Dimeric naphthylisoquinoline (NIQ) alkaloids are an emerging group of structurally, biosynthetically, and pharmacologically intriguing natural products, as yet isolated from African and Asian lianas belonging to the genus Ancistrocladus Wall. (Ancistrocladaceae) exclusively. These metabolites and their monomers are the only known di- and tetrahydroisoquinoline alkaloids that do not originate from aromatic amino acids, but from polyketide precursors.

Ancistrobreveines A-D and related dehydrogenated naphthylisoquinoline alkaloids with antiproliferative activities against leukemia cells, from the West African liana .

A unique series of six biaryl natural products displaying four different coupling types (5,1', 7,1', 7,8', and 5,8') were isolated from the roots of the West African liana (Ancistrocladaceae). Although at first sight structurally diverse, these secondary metabolites all have in common that they belong to the rare group of naphthylisoquinoline alkaloids with a fully dehydrogenated isoquinoline portion. Among the African species, is so far only the second one that was found to produce compounds with such a molecular entity.

Antiprotozoal dimeric naphthylisoquinolines, mbandakamines B and B, and related 5,8'-coupled monomeric alkaloids, ikelacongolines A-D, from a Congolese liana.

From the leaves of a botanically and phytochemically as yet unexplored liana discovered in the rainforests of the Central region of the Democratic Republic of the Congo in the vicinity of the town of Ikela, six new naphthylisoquinoline alkaloids were isolated, , two constitutionally unsymmetric dimers, the mbandakamines B (3) and B (4), and four related 5,8'-linked monomeric alkaloids, named ikelacongolines A-D (5a, 5b, 6, and 7). The dimers 3 and 4 are structurally unusual quateraryls comprising two 5,8'-coupled monomers linked a sterically strongly constrained 6',1''-connection between their naphthalene units. These compounds contain seven elements of chirality, four stereogenic centers and three consecutive chiral axes.

Ancistrobrevines E-J and related naphthylisoquinoline alkaloids from the West African liana Ancistrocladus abbreviatus with inhibitory activities against Plasmodium falciparum and PANC-1 human pancreatic cancer cells.

From the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae), ten new naphthylisoquinoline alkaloids (7a, 7b, 8a, 8b, and 9-14), displaying three different coupling types (5,1', 5,8', and 7,8'), were isolated, among them a series of five 5,1'-linked representatives and four metabolites belonging to the rare group of 7,8'-coupled alkaloids. Two of the alkaloids, the ancistrobrevines I (13) and J (14), are only the fourth and fifth examples of 7,8'-linked naphthyldihydroisoquinolines ever found in nature. The stereostructures of the new plant metabolites were determined by spectroscopic, chemical (oxidative degradation), and chiroptical (electronic circular dichroism) methods.

Ancistrolikokine E, a 5,8'-Coupled Naphthylisoquinoline Alkaloid, Eliminates the Tolerance of Cancer Cells to Nutrition Starvation by Inhibition of the Akt/mTOR/Autophagy Signaling Pathway.

PANC-1 human pancreatic cancer cells are characterized by their ability to proliferate aggressively under hypovascular and hypoxic conditions in the tumor microenvironment, displaying a remarkable tolerance to nutrition starvation. The antiausterity strategy is a new approach in anticancer drug discovery aiming at the identification of potent agents that inhibit preferentially the survival of tumor cells during a limited supply of nutrients and oxygen. The new 5,8'-coupled naphthyldihydroisoquinoline alkaloid ancistrolikokine E (4), isolated from the Congolese liana Ancistrocladus likoko, showed potent preferential cytotoxicity against PANC-1 cells under nutrient-deprived conditions, with a PC value of 2.

Ancistroyafungines A-D, 5,8'- and 5,1'-coupled naphthylisoquinoline alkaloids from a Congolese Ancistrocladus species, with antiausterity activities against human PANC-1 pancreatic cancer cells.

Four new naphthylisoquinoline alkaloids, the 5,8'-coupled ancistroyafungines A-C (1-3) and the 5,1'-linked ancistroyafungine D (4), have been isolated from the stem bark of an as yet unidentified Ancistrocladus (Ancistrocladaceae) liana recently discovered near the village Yafunga, in the North-Central region of the Democratic Republic of the Congo. Likewise obtained were eleven analogs previously identified in related African and Asian Ancistrocladus species, exhibiting five different coupling types, viz., 5,8', 5,1', 7,1', N,6', and N,8'.

Ancistrolikokine I and further 5,8'-coupled naphthylisoquinoline alkaloids from the Congolese liana Ancistrocladus likoko and their cytotoxic activities against drug-sensitive and multidrug resistant human leukemia cells.

The Congolese liana Ancistrocladus likoko (Ancistrocladaceae) produces naphthylisoquinoline alkaloids that are, chemotaxonomically remarkable, all based on the same coupling type, with the biaryl axis located between C-5 and C-8'. About 20 alkaloids, belonging to the subclass of 5,8'-linked naphthylisoquinolines, have so far been discovered in this plant species. Here, we report on the isolation and structure elucidation of six further such 5,8'-coupled monomeric alkaloids, named ancistrolikokines I (9), C (10), F (11), J (12), J (13), and J (14).