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 A3-7 (3-7). These alkaloids have a chemically thrilling structural array consisting of a twisted dihydrofuran-cyclohexenone-isochromene system. The 1'″-epimer of 4, cyclombandakamine A1 (8), had previously been discovered in an unidentified Ancistrocladus species related to A. ealaensis. Both lianas produce the potential parent precursor, mbandakamine A (9), but only A. ealaensis synthesizes the corresponding cyclized form, along with a broad series of slightly modified analogs. The challenging isolation required, besides multi-dimensional chromatography, the use of a pentafluorophenyl stationary phase. Featuring up to six stereocenters and two types of chiral axes, their structures were elucidated by means of 1D and 2D NMR, HRESIMS, in combination with oxidative chemical degradation experiments as well as chiroptical (electronic circular dichroism spectroscopy) and quantum chemical calculations. Compared to the 'open-chain' parent compound 9, these dimers displayed rather moderate antiplasmodial activities.

α-methylation and α-fluorination electronic effects on the regioselectivity of carbonyl groups of uracil by H and triel bonds in the interaction of U, T and 5FU with HCl and TrH3 (Tr = B, Al).

Quantum chemical calculations at the ωB97XD/6-311++G(d,p) level of theory have been executed to investigate the effect of substituents via hydrogen-bonded and triel-bonded complexes between uracil (U), thymine (T) and 5-fluorouracil (5FU) with HCl for the former complexes, and with BH3 and AlH3 for the latter complexes. These calculations are supported by single-point energy calculations at MP2/6-311++G(d,p) and CCSD/6-31 + G(d,p) levels of theory, Natural Bond Orbital (NBO) and Molecular Electrostatic Potentials (MEPs) analyses, and global/local reactivity descriptors. The results reveal that triel-bonded complexes are strongly bounded than hydrogen-bonded ones, and Al-containing dimers stronger than B-containing ones. In addition, as the central triel atom grows in size, B-containing dimers (B-O triel bond) are accompanied by weak B-H⋯O unconventional H-bonds. According to local reactivity descriptors, the B-O triel bond is hard-hard interaction that indicates that the association is primarily charge controlled, while the Al-O triel bond is soft-soft interaction that is primarily orbital controlled. In both Hydrogen as well as triel-bonded complexes, the α-methylation slightly overestimates the binding strength of U, while the α-fluorination exerts the opposite role by underestimating the binding strength of U. In overall, the effect of substituents on the bond strength and thus on the regioselectivity is very small, suggesting a competition between the two carbonyl groups in terms of structures and binding energies.

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), C3 (10), F2 (11), J (12), J2 (13), and J3 (14). They were identified in the twigs of A. likoko, along with the two new atropo-diastereomeric dimers michellamines A8 (15a) and B8 (15b) and the naphthalene-devoid dihydroisoquinoline ent-ealaine D (19). The latter had previously only been known from total synthesis and has now been identified for the first time as an authentic natural product. Three of the new alkaloids, 12-14, are the only fully dehydrogenated naphthylisoquinolines with a 5,8'-biaryl linkage, apart from one single known other example previously likewise found in A. likoko. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR), chemical (oxidative degradation), and chiroptical (electronic circular dichroism) methods. The new ancistrolikokines exhibited moderate to strong cytotoxic activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and against cells of their multidrug-resistant subline, CEM/ADR5000. A first structure-activity relationship (SAR) study on a small library of 5,8'-coupled naphthylisoquinolines from the twigs of A. likoko suggests that the oxygenation patterns in the isoquinoline portion at C-6 and C-8 play a crucial role for the antileukemic activities within this group of alkaloids.

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

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.

Cyclombandakamines A1 and A2, Oxygen-Bridged Naphthylisoquinoline Dimers from a Congolese Ancistrocladus Liana.

Cyclombandakamines A1 (1) and A2 (2), both with an unprecedented pyrane-cyclohexenone-dihydrofuran sequence and six stereocenters and two chiral axes, are the first oxygen-bridged dimeric naphthylisoquinoline alkaloids. They were isolated from the leaves of an as yet unidentified Congolese Ancistrocladus species. Their stereostructures were established by spectroscopic, chemical, and chiroptical methods in combination with DFT and TDDFT calculations. They apparently originate from a cascade of oxidative cyclization reactions of "open-chain" naphthylisoquinoline dimers and exhibit significant antiprotozoal activities.

Mbandakamines A and B, unsymmetrically coupled dimeric naphthylisoquinoline alkaloids, from a Congolese Ancistrocladus species.

Mbandakamines A (1) and B (2), isolated from the leaves of an as yet unidentified Congolese Ancistrocladus species, are the first dimeric naphthylisoquinoline alkaloids with an unsymmetrically coupled central biaryl axis. Their novel 6',1″-coupling type implies a hitherto unprecedented peri-peri coupling in one of the naphthalene parts, leading to the as yet highest steric hindrance at the central axis and a total of seven elements of chirality. Mbandakamine A exhibits good antimalarial activity.

In vitro effects of anthocyanin extracts from Justicia secunda Vahl on the solubility of haemoglobin S and membrane stability of sickle erythrocytes.

BACKGROUND: Sickle cell disease or drepanocytosis is caused by the polymerisation of abnormal haemoglobin S when oxygen tension decreases. This lead to the changes in the shape of red blood cells and anaemia. It has also been postulated that the red cells of patients with sickle cell disease contain a higher than normal concentration of calcium ions. These ions are bound to membrane proteins resulting in dehydration and loss of red blood cell deformability and cell-to-cell adherence. Anthocyanins extracted from some Congolese plants used in traditional medicine against sickle cell disease have recently been shown to have anti-sickling activity in vitro. Justicia secunda is a plant used in Congo by Jehovah's Witnesses, well known for their refusal of blood transfusions, against anaemia. MATERIALS AND METHODS: Emmel, Itano and osmotic fragility tests were used to test the effect of anthocyanin extracts from Justicia secunda leaves on haemoglobin S solubility and sickle cell membrane stability. RESULTS: Anthocyanins from Justicia secunda were found to possess anti-sickling activity. Treated SS red blood cells recovered a normal, classical biconcave form with a radius of 3.3±0.3 µm, similar to that of normal erythrocytes. The solubility of deoxyhaemoglobin S increased and the osmotic fragility of drepanocytes decreased upon treatment with anthocyanin extracts. CONCLUSION: These findings suggest that anthocyanin extracts play a role in both stabilising the red blood cell membrane and inhibiting polymerisation of haemoglobin S. This provides a possible molecular basis for earlier reports on the anti-sickling properties of anthocyanins from some Congolese plants and their use in the management of sickle cell disease by Congolese traditional healers.

Six naphthylisoquinoline alkaloids and a related benzopyranone from a Congolese Ancistrocladus species related to Ancistrocladus congolensis.

From the roots of a recently discovered Ancistrocladus taxon, with close affinities to Ancistrocladus congolensis regarding molecular ITS sequence data, six naphthylisoquinoline alkaloids, 5'-O-demethylhamatine (2), 5'-O-demethylhamatinine (3), 6-O-demethylancistroealaine A (4), 6,5'-O,O-didemethylancistroealaine A (5), 5-epi-6-O-methylancistrobertsonine A (6), and 5-epi-4'-O-demethylancistrobertsonine C (7), have been isolated, along with a likewise benzopyranone carboxylic acid, 8. The structural elucidation succeeded by chemical, spectroscopic, and chiroptical methods. Their bioactivities were tested against protozoan parasites causing severe tropical diseases. Furthermore, eight known related alkaloids were identified.

Ancistrocongolines A-D, new naphthylisoquinoline alkaloids from ancistrocladus congolensis.

Four new naphthylisoquinoline alkaloids, ancistrocongolines A-D (4-7) were isolated from Ancistrocladus congolensis, along with the known compound korupensamine A (8). Structural elucidation was achieved by chemical, spectroscopic, and chiroptical methods. Their biological activities against the pathogens of malaria, Leishmaniasis, Chagas disease, and African sleeping sickness were evaluated.