ABSTRACT
Two new prenylated flavanones, 2 S-3'-(2-hydroxy-3-methylbut-3-enyl)licoflavone-4'-methyl ether ( 3) and 2 S-3'-(2-hydroxy-3-methylbut-3-enyl)abyssinone II ( 4), and four known flavanones ( 1, 2, 5, 6) were isolated from the stem bark of Erythrina addisoniae. The structures were elucidated on the basis of their spectroscopic and physicochemical data. None of the compounds showed antioxidative properties. 4'-Methylabyssinone V ( 1) and abyssinoflavanone VII ( 6) showed moderate cytotoxic activity (IC 50 = 5 and 3.5 micromol/L, respectively), but apoptosis (caspase-3/7-activation, nuclear fragmentation) was selectively induced by abyssinoflavanone VII ( 6).
Subject(s)
Apoptosis/drug effects , Erythrina/chemistry , Flavanones/isolation & purification , Animals , Flavanones/chemistry , Flavanones/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Plant Bark/chemistry , RatsABSTRACT
The genus Erythrina (Leguminosae), consisting of over 100 different species, is distributed in tropical regions. In traditional medicine, Erythrina species are used to treat cancer, but little is known about the anticancer mechanisms. From the stem bark of Erythrina addisoniae Hutch. & Dalziel, six prenylated pterocarpans were isolated and analysed for pharmacological activity: While calopocarpin, cristacarpin, orientanol c, and isoneorautenol showed only a weak or moderate toxicity in H4IIE hepatoma cells (EC(50)-value> 25 microM), the toxicity of neorautenol and phaseollin was in the low micromolar range (EC(50)-value: 1 and 1.5 microM, respectively). We further focused on these two substances showing that both increased caspase 3/7 activity and nuclear fragmentation as markers for apoptotic cell death. Neorautenol (10 microM, 2h), but not phaseollin induced the formation of DNA strand breaks (comet assay). Both substances showed no effect on NF-kappaB signalling (SEAP assay: basal activity and stimulation with TNF-alpha), on the other hand both pterocarpans (10 microM, 2 h) decreased the activation of the ERK kinase (p44/p42), an mitogen activated protein kinase which is associated with cell proliferation. We conclude that the pterocarpans phaseollin and neorautenol may be responsible for the anticarcinogenic actions of the plant extract reported in the literature. Further analysis of these substances may lead to new pharmacons to be used in cancer therapy.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Erythrina , Extracellular Signal-Regulated MAP Kinases/metabolism , Isoflavones/pharmacology , Plant Extracts/pharmacology , Pterocarpans/pharmacology , Signal Transduction/drug effects , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Cell Survival/drug effects , DNA Breaks, Single-Stranded , Dose-Response Relationship, Drug , Enzyme Activation , Erythrina/chemistry , Inhibitory Concentration 50 , Isoflavones/isolation & purification , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , NF-kappa B/metabolism , Necrosis , Phosphorylation , Plant Bark , Plant Extracts/isolation & purification , Prenylation , Pterocarpans/isolation & purification , Pterocarpans/toxicity , RatsABSTRACT
The indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of beta-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg(-1) day(-1) ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (DeltaT(m) value) or toxicity in the mouse-malaria model.
Subject(s)
Alkaloids/chemistry , Alkaloids/chemical synthesis , Antimalarials/chemical synthesis , Indoles , Quinolines , Alkaloids/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cattle , DNA/chemistry , Drug Screening Assays, Antitumor , Heating , Hemin/chemistry , Indole Alkaloids , Malaria/drug therapy , Mice , Nucleic Acid Denaturation , Plasmodium berghei , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Fourteen Ghanaian plants used in folk medicine to treat fever/malaria were screened for activity against Plasmodium falciparum (strain K1) and were tested for general toxicity to the brine shrimp. Extracts from three of the plants, Pleiocarpa mutica, Cleistopholis patens and Uvaria chamae were found to have significant antiplasmodial activity. The extract of U. chamae was toxic to brine shrimps. These findings lend support to the use of these plants in traditional medicine. Possible toxicity due to U. chamae is a cause for concern. Five known alkaloids, pleiocarpine (1), kopsinine (2), pleiocarpamine (3), eburnamine (4) and pleiomutinine (5) were isolated from the roots of P. mutica. This is the first report of the occurrence of (4) in P. mutica. Compound (5) was the most active against P. falciparum (IC50 = 5 microM). Although (1) was inactive against malaria parasites in vitro, it was moderately active against P. berghei in mice (25 mg kg(-1) daily for 4 days reduced parasitaemia by 28.5% compared to untreated controls).
