A Near-Complete Series of Four Atropisomeric Jozimine A2-Type Naphthylisoquinoline Dimers with Antiplasmodial and Cytotoxic Activities and Related Alkaloids from Ancistrocladus abbreviatus.

Three new naphthylisoquinoline dimers, jozibrevines A-C (1a-c), were isolated from the West African shrub Ancistrocladus abbreviatus, along with the known dimer jozimine A2 (1d). The two molecular moieties of 1a-d 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, 1a-d possess three consecutive stereogenic axes. The four isolated dimers all have the same constitutions and identical absolute configurations at the four stereogenic centers, but differ by their axial chirality. They belong to the extremely small class of Dioncophyllaceae-type naphthylisoquinoline dimers, i.e., being devoid of oxygen functions at C-6 and bearing the R-configuration at C-3 in their isoquinoline portions. Besides these dimers, the plant produces predominantly typical Ancistrocladaceae-type monomeric compounds, i.e., with the S-configuration at C-3 and an oxygen function at C-6, such as the new ancistrobrevines K (5) and L (6). Furthermore, a new hybrid-type (i.e., mixed Ancistrocladaceae/Dioncophyllaceae-type) alkaloid was identified, named ancistrobrevine M (7), which is 3R-configured and 6-oxygenated. Remarkable was the discovery of its "inverse hybrid-type" counterpart, dioncoline A (8). It is the as yet only known 3S-configured naphthylisoquinoline lacking an O-functionality at C-6. The new jozibrevines A-C (1a-c) exhibited pronounced antiplasmodial activities in the submicromolar range, with 1a being the most potent compound (IC50, 0.012 μM). Furthermore, jozimine A2 (1d) showed cytotoxicity against human colon carcinoma (HT-29), fibrosarcoma (HT1080), and multiple myeloma (MM.1S) cancer cells, displaying IC50 values of 12.0, 9.0, and 5.0 μM, respectively, whereas jozibrevines A (1a) and B (1b) were nontoxic in this concentration range.

[1]  D. Feineis,et al.  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. , 2018, Fitoterapia.

[2]  H. Wajant,et al.  Soluble TNF-like weak inducer of apoptosis (TWEAK) enhances poly(I:C)-induced RIPK1-mediated necroptosis , 2018, Cell Death & Disease.

[3]  T. Efferth,et al.  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. , 2018, Fitoterapia.

[4]  T. Efferth,et al.  Mbandakamine-Type Naphthylisoquinoline Dimers and Related Alkaloids from the Central African Liana Ancistrocladus ealaensis with Antiparasitic and Antileukemic Activities. , 2018, Journal of natural products.

[5]  D. Feineis,et al.  Antiprotozoal Spirombandakamines A1 and A2, Fused Naphthylisoquinoline Dimers from a Congolese Ancistrocladus Plant. , 2017, Organic letters.

[6]  D. Feineis,et al.  Jozilebomines A and B, Naphthylisoquinoline Dimers from the Congolese Liana Ancistrocladus ileboensis, with Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Cell Line. , 2017, Journal of natural products.

[7]  T. Efferth,et al.  Antileukemic ancistrobenomine B and related 5,1'-coupled naphthylisoquinoline alkaloids from the Chinese liana Ancistrocladus tectorius. , 2017, Fitoterapia.

[8]  D. Feineis,et al.  Antiplasmodial Ealapasamines A-C,‘Mixed’ Naphthylisoquinoline Dimers from the Central African Liana Ancistrocladus ealaensis , 2017, Scientific Reports.

[9]  D. Feineis,et al.  Cyclombandakamines A1 and A2, Oxygen-Bridged Naphthylisoquinoline Dimers from a Congolese Ancistrocladus Liana. , 2017, Organic letters.

[10]  T. Efferth,et al.  Dioncophyllines C2, D2, and F and Related Naphthylisoquinoline Alkaloids from the Congolese Liana Ancistrocladus ileboensis with Potent Activities against Plasmodium falciparum and against Multiple Myeloma and Leukemia Cell Lines. , 2017, Journal of natural products.

[11]  D. Feineis,et al.  HIV-inhibitory michellamine-type dimeric naphthylisoquinoline alkaloids from the Central African liana Ancistrocladus congolensis. , 2016, Phytochemistry.

[12]  D. Feineis,et al.  5′- O -Methyldioncophylline D, a 7,8′-coupled naphthylisoquinoline alkaloid from callus cultures of Triphyophyllum peltatum , and its biosynthesis from a late-stage tetrahydroisoquinoline precursor , 2016 .

[13]  G. Mohamed,et al.  Naphthylisoquinoline alkaloids potential drug leads. , 2015, Fitoterapia.

[14]  G. Bringmann,et al.  Mbandakamines A and B, unsymmetrically coupled dimeric naphthylisoquinoline alkaloids, from a Congolese Ancistrocladus species. , 2013, Organic letters.

[15]  G. Bringmann,et al.  SpecDis: quantifying the comparison of calculated and experimental electronic circular dichroism spectra. , 2013, Chirality.

[16]  T. Kupfer,et al.  Jozimine A2: the first dimeric Dioncophyllaceae-type naphthylisoquinoline alkaloid, with three chiral axes and high antiplasmodial activity. , 2013, Chemistry.

[17]  T. Renner,et al.  A Sticky Situation: Assessing Adaptations for Plant Carnivory in the Caryophyllales by Means of Stochastic Character Mapping , 2011, International Journal of Plant Sciences.

[18]  G. Bringmann,et al.  Shuangancistrotectorines A-E, dimeric naphthylisoquinoline alkaloids with three chiral biaryl axes from the Chinese plant Ancistrocladus tectorius. , 2010, Chemistry.

[19]  D. Taşdemir,et al.  Inhibitory Activity of Marine Sponge-Derived Natural Products against Parasitic Protozoa , 2010, Marine drugs.

[20]  Solomon Nwaka,et al.  Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression , 2009, PLoS neglected tropical diseases.

[21]  G. Bringmann,et al.  Six naphthylisoquinoline alkaloids and a related benzopyranone from a Congolese Ancistrocladus species related to Ancistrocladus congolensis. , 2008, Phytochemistry.

[22]  G. Bringmann,et al.  Biosynthesis of naphthylisoquinoline alkaloids: synthesis and incorporation of an advanced 13C2-labeled isoquinoline precursor , 2007 .

[23]  G. Bringmann,et al.  Molecular phylogeny and character evolution of carnivorous plant families in Caryophyllales--revisited. , 2006, Plant biology.

[24]  M. Wohlfarth,et al.  ent-Dioncophylleine A and related dehydrogenated naphthylisoquinoline alkaloids, the first Asian dioncophyllaceae-type alkaloids, from the "new"plant species Ancistrocladus benomensis. , 2005, Journal of natural products.

[25]  G. Bringmann,et al.  Ancistrobenomine a, the first naphthylisoquinoline oxygenated at Me-3, and related 5,1'-coupled alkaloids, from the "new" plant species ancistrocladusbenomensis. , 2004, Journal of Natural Products.

[26]  S. Christensen,et al.  Ancistrotanzanine C and related 5,1'- and 7,3'-coupled naphthylisoquinoline alkaloids from Ancistrocladus tanzaniensis. , 2004, Journal of natural products.

[27]  S. Christensen,et al.  Ancistrotanzanine A, the first 5,3'-coupled naphthylisoquinoline alkaloid, and two further, 5,8'-linked related compounds from the newly described species Ancistrocladus tanzaniensis. , 2003, Journal of natural products.

[28]  G. Bringmann,et al.  Two Atropisomeric N-Methyldioncophyllines A and N-Methylphylline, their Naphthalene-Free Heterocyclic Moiety, from Ancistrocladus barteri , 2003 .

[29]  M. Wohlfarth,et al.  A photometric screening method for dimeric naphthylisoquinoline alkaloids and complete on-line structural elucidation of a dimer in crude plant extracts, by the LC-MS/LC-NMR/LC-CD triad. , 2001, Analytical chemistry.

[30]  M. Cheek.  A Synoptic Revision of Ancistrocladus (Ancistrocladaceae) in Africa, with a New Species from Western Cameroon , 2000 .

[31]  M. Boyd,et al.  Michellamines D-F, new HIV-inhibitory dimeric naphthylisoquinoline alkaloids, and korupensamine E, a new antimalarial monomer, from Ancistrocladus korupensis. , 1997, Journal of natural products.

[32]  J. Holenz,et al.  Naphthylisoquinoline alkaloids exhibit strong growth-inhibiting activities against Plasmodium falciparum and P. berghei in vitro--structure-activity relationships of dioncophylline C. , 1996, Annals of tropical medicine and parasitology.

[33]  M. Boyd,et al.  Dioncophylline A, the Principal Cytotoxin from Ancistrocladus letestui , 1995 .

[34]  J. Clardy,et al.  Korupensamines A-D, Novel Antimalarial Alkaloids from Ancistrocladus korupensis , 1994 .

[35]  Victor A. Albert,et al.  Relationships of Droseraceae: A cladistic analysis of RBCL sequence and morphological data , 1994 .

[36]  M. Boyd,et al.  Anti-HIV michellamines from Ancistrocladus korupensis. , 1994, Journal of medicinal chemistry.

[37]  G. Bringmann,et al.  Ancistrobarterine A: A New “Mixed” Ancistrocladaceae/Dioncophyllaceae-Type Alkaloid from Ancistrocladus barteri , 1993 .

[38]  G. Bringmann,et al.  Ancistrobrevine C from Ancistrocladus abbreviatus: The first mixed ‘ancistrocladaceae/dioncophyllaceae-type’ naphthylisoquinoline alkaloid , 1993 .

[39]  G. Bringmann,et al.  Dioncoline A and its Atropisomer: “Inverse Hybrid Type” Ancistrocladaceae/Dioncophyllaceae Alkaloids from Ancistrocladus abbreviatus , 1992 .

[40]  M. Boyd,et al.  Novel alkaloids from the tropical plant Ancistrocladus abbreviatus inhibit cell killing by HIV-1 and HIV-2. , 1991, Journal of medicinal chemistry.

[41]  H. K. A. Shaw.  Further Notes on West African Ancistrocladus , 1950 .