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Cytotoxic Aporphine Alkaloids from Cassytha filiformis
Abstract
Purification of a cytotoxic crude alkaloid extract of Cassytha filiformis led to the isolation of four known aporphine alkaloids: neolitsine, dicentrine, cassythine (= cassyfiline) and actinodaphnine. Their structures were determined by analysis of spectroscopic data. All isolated alkaloids were tested for their cytotoxic activities on cancer and non-cancer cell lines in vitro. Neolitsine was the most active against HeLa and 3T3 cells (IC 50 :21.6 microM, and 21.4 microM, respectively). Cassythine and actinodaphnine showed the highest activity against Mel-5 (IC 50 : 24.3 microM and 25.7 microM, respectively) and HL-60 (IC 50 : 19.9 microM and 15.4 microM, respectively). This is the first report on the cytotoxic activity of C. filiformis extract and of neolitsine and cassythine. Furthermore, the complete NMR data of cassythine and actinodaphnine are given here for the first time.
... The alkaloids actinodaphnine (8) and dicentrine (9) present a dioxymethylene at C-1 and C-2, whereas reticuline (15), a benzyltetrahydroisoquinoline alkaloid, also has two hydroxyls at C-7 and C-11, two methoxyls at C-6 and C-10 and a methyl at the nitrogen atom. Among the aporphine structures, actinodaphnine (8), laurolitsine (11), boldine (12), laurotetanine (13) and N-methyllaurotetanine (14) present a hydroxyl at C-9. Laurolitsine (11) has a methyl at C-10, whereas laurolitsine (11), boldine (12), laurotetanine (13), N-methyllaurotetanine (14) and isocorydine (16) have a methoxyl at C-1. Laurolitsine (11) and boldine (12) have a hydroxyl at C-2, and laurotetanine (13), Nmethyllaurotetanine (14) and isocorydine (16) have a methoxyl at C-2. ...
... The alkaloids actinodaphnine (8) and dicentrine (9) present a dioxymethylene at C-1 and C-2, whereas reticuline (15), a benzyltetrahydroisoquinoline alkaloid, also has two hydroxyls at C-7 and C-11, two methoxyls at C-6 and C-10 and a methyl at the nitrogen atom. Among the aporphine structures, actinodaphnine (8), laurolitsine (11), boldine (12), laurotetanine (13) and N-methyllaurotetanine (14) present a hydroxyl at C-9. Laurolitsine (11) has a methyl at C-10, whereas laurolitsine (11), boldine (12), laurotetanine (13), N-methyllaurotetanine (14) and isocorydine (16) have a methoxyl at C-1. Laurolitsine (11) and boldine (12) have a hydroxyl at C-2, and laurotetanine (13), Nmethyllaurotetanine (14) and isocorydine (16) have a methoxyl at C-2. ...
... High cytotoxicity was observed for actinodaphnine (8) using the Mel-5 and HL-60 cell lines. 16 This alkaloid also induced apoptosis in the human hepatoma cells Mahlavu by increasing nitric oxide and reactive oxygen species and modulating NF-kB signalling. 18 Dicentrine (9) showed cytotoxic activity in the HCE-6, Molt-4, CESS, HL60, K562 and MS-G2 cell lines. ...
Lauraceae is one of the most representative botanical families, presenting 67 genera, with over 2500 species and more than 300 different alkaloids reported, mainly isoquinolines. Its diversity and relevance to chemosystematic relationships is presented and discussed.
... Many studies have proven that this herbaceous plant exhibits antiplatelet and vasorelaxing effect, 10 antihypertensive, 11-12 diuretic effect 13 and blood glucose lowering effect. 14 Other studies have also confirmed different effects of the plant, including uterotonic, 15 anticancer, [16][17] immunosuppressive 18 and anti-infectious. 17,[19][20] These properties make this plant a very promising herbal medicine for the development of pharmaceuticals. ...
... Toxic effect of this extract is also reported by Quetin et al. who describes that the alkaloid contents of this plant exhibit cytotoxic activity with a non-specific topoisomerase I and II inhibition mechanism. [16][17] This non-selective inhibition may also affect the normal liver cells and cause cell damage. 34 Fortunately, the toxic effect on the liver function is reversible, indicated by the decrease of mice ALT and ALP on day 3 to 7 after the extract was discontinued, depending on dose. ...
Objective: To study the liver toxicity of Cassytha filiformis L. extract and its reversibility in mice. Methods: A total of 108 male mice were used to investigate the hepatotoxicity of Cassytha filiformis extract (CFE) and the reversibility of its toxicity to the liver. Seventy-two mice were treated with CFE orally for 7 consecutive days. A half of these animals were used to study the sleep time on propofol-induced sleep that comprised the sleep onset time (SOT) and duration of sleep (DOS), while another half was used for the quantitation of serum alanine transaminase (ALT) activity. To investigate the reversibility of the liver toxicity, thirty-six mice were treated with daily CFE for 7 days. Activities of ALT and alkaline phosphatase (ALP) were determined and the liver weight ratio was measured on day 0, 1, 3 and 7 after the termination of the CFE treatment. Data of liver toxicity determination were analyzed by two-way ANOVA followed by Duncan's multiple range test, while data of the reversibility was analyzed by Pearson's correlation. The significance level was taken at 95% of confidence interval. Results: CFE shortened the SOT and prolonged the DOS significantly compared with control (p<0.05). The activity of ALT was increased due to the toxicity of CFE. However, the ALT/ALP activities decreased and liver weight ratio increased gradually after the extract treatment was discontinued. The trend of these data was correlated significantly (p<0.05). Conclusion: Cassytha filiformis L. extract is toxic to the liver but the toxicity is reversible depending on doses.
... The molecular weight (M 311 Da) was determined by GC-MS and it was compatible with the molecular formula C 18 H 17 O 4 N. The structure of actinodaphine (4) was attributed based on the comparison of NMR spectral data with values reported in the literature (Stévigny et al., 2002). It is possible to observe the presence of two apparent singlets at 5.86 and 6.01 ppm that were attributed to the hydrogens in the methylenedioxy in position 1, 2. The presence of a singlet referent to 3H in 3.85 ppm may correspond to a methoxy group as a substituent at carbon 10. ...
... With these observations, it was possible to attribute that compound 4 is actinodaphnine. The attributions of the J values were compared to results found in the literature (Stévigny et al., 2002). The purity grade of the sample permitted its analysis with different carbon NMR experiments to confirm the structure. ...
Annona hypoglauca Mart.,Annonaceae, popularly known as "beriba", was collected in flooded areas of the Amazonian Rain Forest. The crude extract obtained from this species was found to be cytotoxic against human cancer cells. Chemical information on A. hypoglauca is scarce. So, the present work aimed the isolation and identification of its alkaloids and to test their cytotoxic activity. Alkaloids were obtained from stem by acid-base partitioning and the remaining alkaloid-free extract was partitioned with organic solvents. Gas chromatography-mass spectrometry GC/MS analysis of total alkaloids allowed the identification of four aporphine alkaloids: actinodaphnine, anonaine, isoboldine and nornuciferine. Total alkaloids were fractionated by column chromatography and were purified by preparative thin-layerchromatography, which allowed the isolation of two aporphine alkaloids, actinodaphnine and isoboldine, characterized by NMR and CG-MS analyses. This is the first report for the occurrence of actinodaphninein Annona species. All the samples were tested in cytotoxic and antibacterial assays. Total alkaloid extract and its fractions showed antimicrobial activity against Staphylococcus aureus and Enterococcus faecalis. In the cytotoxicity assay, the crude extract showed a lethal effect against breast and colon cancer cells. Isoboldine-containing FA5 and actinodaphnine-containing FA6 showed activity against breast cancer cell line, while the alkaloid-free fractions did not show significant activity against cancer cell lines. (C) 2016 Sociedade Brasileira de Farmacognosia. Published by Elsevier Editora Ltda.
... The cytotoxicity of the MeOH extract of M. lucida and its fractions was evaluated on WI38 cells (non-cancerous human fibroblast cell line) using the MTT assay. The methodology used was as described in the literature (St evigny et al., 2002;Tchetan et al., 2023;. Cells were seeded in 96-well plates (5000 cells/well) overnight in DMEM (Dulbecco's Modified Eagle's Medium supplemented with 10% inactivated fetal calf serum and 1% penicillin/streptomycin). ...
Morinda lucida Benth (Rubiaceae) is a medicinal plant traditionally used to treat malaria and digestive parasitosis. In vitro pharmacological studies have shown that extracts of the plant were very active against nematodes. The aim of our work was to identify the compounds responsible for the anthelmintic activity of M. lucida. To achieve this, the leaf MeOH extract was fractionated and the anthelmintic activity of the fractions was evaluated on Haemonchus contortus and Caenorhabditis elegans and their cytotoxicity was evaluated on WI38 cells. The fractions were analyzed by HPLC-HRMS/MS and manual dereplication was coupled to molecular networking to identify the major compounds in the most active fractions. The results showed that three fractions, F8, F11, and F13 were the most active on both nematode models and less cytotoxic. In total, sixteen different compounds were putatively identified in these three fractions, 9 in F8, 12 in F11 and 12 in F13, as some are present in different fractions. Among these compounds, ten were identified for the first time in M. lucida. These are mainly iridoids including loganic acid (2) and isomer (4),methoxygaertneroside or isomer (14),dehydromethoxygaertneroside or isomer (18), borreriagenin (3) and isomer (5). We also identified flavonoids including rutin pentoside (10), kaempferol-3-O-rutinoside pentoside(12), and kaempferol-3-O-rutinoside (15).The Bioactivity-Based approach identified loganic acid or isomer I (2), asperulosidic acid or isomer (6),methoxygaertneroside or isomer (14), and kaempferol-3-O-rutinoside or isomer (15) as potential compounds responsible for the anthelmintic activity of the three fractions. However, it seems necessary to quantify them and evaluate the anthelmintic activity of each of these compounds in order to confirm the results of the Bioactivity-based approach and to identify potential new anthelmintic molecules to prevent resistance development. Furthermore, possible synergy between them also has to be analyzed.
... Cytotoxicity of the fractions was evaluated on WI38 cells (non-cancerous human fibroblast cell line) using MTT-assay according to a procedure described in the literature [42]. They were solubilized in DMSO at a concentration of 20 mg/mL. ...
Terminalia leiocarpa is a medicinal plant widely used in ethnoveterinary medicine to treat digestive parasitosis whose extracts were shown to be active against gastrointestinal nematodes of domestic ruminants. The objective of our study was to identify compounds responsible for this activity. Column fractionation was performed, and the activity of the fractions was assessed in vitro on Haemonchus contortus and Caenorhabditis elegans as well as their cytotoxicity on WI38 fibroblasts. Two fractions were the most active on both nematode models and less cytotoxic. LC-MS/MS analysis and manual dereplication coupled to molecular networking allowed identification of the main compounds: ellagic acid and derivatives, gallic acid, astragalin, rutin, quinic acid, and fructose. Other potentially identified compounds such as shikimic acid, 2,3-(S)-hexahydroxydiphenoyl-D-glucose or an isomer, quercetin-3-O-(6-O-galloyl)-β-D-galactopyranoside or an isomer, and a trihydroxylated triterpenoid bearing a sugar as rosamultin are reported in this plant for the first time. Evaluation of the anthelmintic activity of the available major compounds showed that ellagic and gallic acids were the most effective in inhibiting the viability of C. elegans. Their quantification in fractions 8 and 9 indicated the presence of about 8.6 and 7.1 µg/mg ellagic acid and about 9.6 and 2.0 µg/mg gallic acid respectively. These concentrations are not sufficient to justify the activity observed. Ellagic acid derivatives and other compounds that were found to be positively correlated with the anthelmintic activity of the fractions may have additive or synergistic effects when combined, but other unidentified compounds could also be implicated in the observed activity.
... The cytotoxicity of crude extracts was evaluated on WI38 cells (human noncancerous fibroblast cell lines) (obtained from LGC standards, Molsheim, France) following the methodology described by Stévigny et al. [33]. Solubilized extracts were diluted in culture medium to obtain tested concentration. ...
Citation: Tchetan, E.; Olounladé, P.A.; Azando, E.V.B.; Khaliq, H.A.; Ortiz, S.; Houngbeme, A.; Alowanou, G.G.; Koura, B.I.; Akouedegni, G.C.; Houinato, M.R.B.; et al. Anthelmintic
... The cytotoxicity of crude extracts was evaluated on WI38 cells (human noncancerous fibroblast cell lines) (obtained from LGC standards, Molsheim, France) following the methodology described by Stévigny et al. [33]. Solubilized extracts were diluted in culture medium to obtain tested concentration. ...
Simple Summary
In the present study, we explored the anthelmintic activity, cytotoxicity, and chemical composition of the main plants used by small ruminant breeders in Benin to treat digestive parasitosis. The results obtained are relevant in the sense that they will allow a rational use of the plants studied in the control of digestive parasites but also to initiate the process of identification of new anthelmintic molecules in the context of the development of resistance against the most currently used anthelmintic molecules.
Abstract
Medicinal plants continue to be used alone or in combination with veterinary drugs to treat animal ailments, especially in developing countries where livestock farmers often lack access to modern veterinary services and drugs. In addition, digestive parasitosis remain a major constraint for small ruminant livestock. The objective of this study was to screen the anthelmintic activity of the main plants used in the treatment of the digestive parasitosis of small ruminants in Benin. A total of 40 extracts were prepared using the successive maceration of 10 plants in four solvents of increasing polarity. The phytochemical screening of the plants was performed, and the anthelmintic activity of the extracts was evaluated on L3 larvae of Haemonchus contortus. The cytotoxicity of the 40 extracts was determined on WI38 noncancerous fibroblast cells using the MTT assay, and the total phenol content (TPC), total flavonoid content (TFC), and condensed tannin content (CTC) were quantified in the most effective extracts using colorimetric methods. The results show that the plants contained tannins, flavonoids, and triterpenoids which may, in part, justify their anthelmintic activities. All plants gave active extracts at the highest concentration tested (1200 µg/mL). Methanol (MeOH) extracts were, in general, more effective than the hexane (HEX), dichloromethane (DCM), and aqueous (H2O) ones in inhibiting larval migration, with the MeOH extracts of Terminalia leiocarpa, Adansonia digitata, and Momordica charantia being the most effective. Nevertheless, the MeOH extract of M. charantia was highly cytotoxic at the concentration of 100 µg/mL. The anthelmintic activity of M. charantia, Vitex doniana, and Caesalpinia bonduc was studied on H. contortus for the first time. These results provide scientific information that can be used for better valorization of the anthelmintic potential of the studied plants and to initiate the process of the identification of new anthelmintic molecules.
... [28] The cytotoxicity test was based on the mitochondrial activity assessment with the MTT tetrazolium salt dye. [29] All pure compounds were solubilized in DMSO at a 10 mg ml À 1 stock solution and tested in 96-well microtiter plates in eight serial three-fold dilutions (concentration range: 50-0.02 μg ml À 1 on parasites and 100-0.05 ...
Research for innovative drugs is crucial to contribute to parasitic infections control and eradication. Inspired by natural antiprotozoal triterpenes, a library of 12 hemisynthetic 3‐O‐arylalkyl esters was derived from ursolic and oleanolic acids through one‐step synthesis. Compounds were tested on Trypanosoma, Leishmania and the WI38 cell line alongside with a set of triterpenic acids. Results showed that the triterpenic C3 esterification keeps the antitrypanosomal activity (IC50≈1.6–5.5 μm) while reducing the cytotoxicity compared to parent acids. Unsaturation of the ester alkyl chain leads to an activity loss interestingly kept when a sterically hindered group replaces the double bond or shields the ester group. An ursane/oleanane C3 hydroxylation was the only important feature for antileishmanial activity. Two candidates, dihydrocinnamoyl and 2‐fluorophenylpropionyl ursolic acids, were tested on an acute mouse model of African trypanosomiasis with significant parasitemia reduction at day 5 post‐infection for the dihydrocinnamoyl derivative. Further evaluation on other alkyl/protective groups should be investigated both in vitro and in vivo. A library of 12 C3 triterpenic esters was readily synthesized and tested for antiparasitic activity and cytotoxicity evaluation. C3 esterification kept the activity while lowering the cytotoxicity. The most potent antitrypanosomal activity, coupled with great selectivity, was shown by 2‐fluoro phenylpropionate, phenylpropionate and α‐methyl phenylpropionate esters of ursolic acids. The phenylpropionate derivative showed significant in vivo parasitemia reduction at day 5 post‐infection.
... This protective effect could be mediated by the antioxidant property of boldine molecule (Jiménez et al., 2000;Santanam et al., 2004). On the other hand, cytotoxicity of aporphine alkaloids from Cassytha filiformis and Ocotea acutifolia (Lauraceae) against several cancer and non-cancer lines has been observed (Stévigny et al., 2002;Garcez et al., 2011) (Supplementary Fig. 2). ...
Peumus boldus is an endemic tree species from Chile whose leaves have been the focus of study for decades given that their infusions are reported to relieve rheumatic symptoms, headache, dyspepsia, urinary tract inflammation, and symptoms of other illnesses. These health properties have been studied mainly using leaves and bark, then it is relevant to know more about these properties in different parts of the plant. Considering the importance of P. boldus fruits in the diet of some rural populations, we analyzed their properties to explore its impact on the Chilean population health. Liquid chromatography and mass spectrometry analysis confirmed the presence of alkaloids such as boldine, although aporphine N-methyl-laurotetanine was the most abundant. In addition, flavonoids catechin, chrysin and quercetin were also found in the extract. Cytotoxicity and anti-inflammatory activities of the fruit extract were in-vitro tested by using a murine macrophage cell model, observing that a diluted fraction of the extract was not cytotoxic, but showed anti-inflammatory activity, which is likely attributed to antioxidants activities. By means of quantum chemical calculations, we calculated the redox potential of the respective alkaloids and flavonoids found in the extract. Results suggest a synergistic effect between alkaloids and flavonoids, where boldine and N-methyl-laurotetanine showed similar antioxidant properties. Finally, we present a description of the oxidation mechanisms for both groups of molecules which will sustain P. boldus fruit biological properties, in order to give this kind of fruits scientific value focusing on human health.
... C. filiformis is used in African ethnomedicine to treat cancer and malaria [5,59]. Various compounds, mainly alkaloids, isolated from the aerial parts of the plant, have cytotoxic activity towards various cancer cell lines [60]. Other compounds from C. filiformis that have exhibited cytotoxic activity against cancer cells include bulbocapnine, cassythine, dicentrine and neolitsine [59,216]. ...
Cancer is a leading cause of death globally, while malaria is the leading cause of death from parasitic diseases in Nigeria. Historically, plant remedies have been used to manage both cancer and malaria. Interestingly, the possibility of treating cancer with antimalarial remedies has long been reported, even though the two diseases appear to have little in common. However, a body of research has indicated the potential anticancer activity of both synthetic and nature-derived antimalarials. In Nigeria, over 100 plants are used for the management of malaria, but little is known for their potential role in combatting cancer. Therefore, this review is to highlight the documented anticancer activities of plants used to treat malaria in Nigeria, with the goal of supporting anticancer drug discovery. Scientific databases were used to search for antimalarial plants using selected keywords. Of over 100 plants used to treat malaria in Nigeria, 56 have documented anticancer properties, containing alkaloids, flavonoids, tannins, terpenes, terpenoids, quinones, anthraquinones, saponins, steroids, sterols, organosulfur compounds and other polyphenols as the major bioactive components. The major mechanisms of anticancer activity include induction of apoptosis and autophagy, arrest of cell growth, generation of reactive oxygen species and inhibition of angiogenesis. However, mechanistic and clinical investigations of the anticancer properties of most of these plants are still lacking. Notwithstanding, the huge anticancer potential uncovered by the in vitro or in vivo studies and a few clinical studies, Nigerian antimalarial plants may provide a valuable resource, ready to be harnessed for anticancer drug development.
... Stevigny et al. evaluated the cytotoxicity of compounds IX, X, XI, and XII on another cancer line cell in vitro [123]. Specifically, when cytotoxic assay on the MeI-5 cell line was conducted, X showed the highest activity against cancer cells with an IC 50 value of 24.3 µM and XI with 25.7 µM. ...
Cancer is a disease that involves impaired genome stability with a high mortality index globally. Since its discovery, many have searched for effective treatment, assessing different molecules for their anticancer activity. One of the most studied sources for anticancer therapy is natural compounds and their derivates, like alkaloids, which are organic molecules containing nitrogen atoms in their structure. Among them, oxoisoaporphine and sampangine compounds are receiving increased attention due to their potential anticancer effects. Boldine has also been tested as an anticancer molecule. Boldine is the primary alkaloid extract from boldo, an endemic tree in Chile. These compounds and their derivatives have unique structural properties that potentially have an anticancer mechanism. Different studies showed that this molecule can target cancer cells through several mechanisms, including reactive oxygen species generation, DNA binding, and telomerase enzyme inhibition. In this review, we summarize the state-of-art research related to oxoisoaporphine, sampangine, and boldine, with emphasis on their structural characteristics and the relationship between structure, activity, methods of extraction or synthesis, and anticancer mechanism. With an effective cancer therapy still lacking, these three compounds are good candidates for new anticancer research
... The cytotoxicity of the oils against CHO and WI38 cells was evaluated as described by Stevigny et al. (2002), using the tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (Sigma)) colorimetric method based on the cleavage of the reagent by dehydrogenases in viable cells. Camptothecin (Sigma) was used as positive cytotoxic reference compound. ...
The uncontrolled use of antimicrobials leads to an increase in the resistance of bacteria which becomes a public health problem. To overcome this problem, our study aims to establish a link between chemical composition and antimicrobial activity and then evaluate cytotoxicity, of seven essential oils. Antimicrobial activity of essential oils was assessed by macrodilution and solid-medium diffusion method on agar, then cytotoxicity test was evaluated in vitro by MTT method. Results showed that essential oils of Cymbopogon schoenantus, Cymbopogon giganteus, Cymbopogon citratus and Citrus aurantifolia are the most bactericidal. Analysis of antimicrobial activity and chemical composition reveal that the essential oil of Eucalyptus camaldulensis, the least oxygenated (14.9%), is the least active. The other essential oils, which are more active, are all rich in oxygenated compound (28.4% to 87.0%). The cytotoxicity assessment shows that our essential oils are less cytotoxic than camptothecin.
... For assessing the cytotoxicity or anticancer activity of the lichen extracts, we used a well-established colorimetric MTT assay 13 . Vero (ATCC CCL-81), MCF7 (ATCC HTB-22), HeLa (ATCC CRM-CCL-2) and WiDr (ATCC CCL-218) cells were seeded in a 96-well plate at a density of 1x104 cells/well and allowed to adhere for 24 hours at 37 o C in a CO 2 incubator. ...
Lichen is a unique composite organism that arises from algae and fungi symbiotic relationship. There are 18,500 recorded lichen species worldwide but only limited number of global species has been tested for their biological activities. In particular, Indonesian lichens are rarely investigated. In this study, we collected and identified nine lichen species from six different locations in East Java Indonesia and screened their crude methanol extracts against gram-negative bacteria (Pseudomonas aeruginosa) and cancer cells (MCF7, Widr and Hela). While only the methanol extract of Parmelia cetrata Ach and Parmelia dilatata Vain inhibited Pseudomonas aeruginosa, most lichen extracts possessed moderate cytotoxicity. Cladonia scabriuscula methanol extract was cytotoxic against MCF7, Widr and Hela cell lines with IC 50 value of 324, 324, 476 μg/mL, respectively. Moreover, methanol extract of Physcia cf. millegrana Degel indicated cytotoxicity against Hela cell line with IC 50 value of 137 μg/mL. This study revealed anticancer potency of lichen of Java Island for the first time and further research is necessary for isolating the bioactive compounds.
... Various compounds such as alkaloids, aporphines, lignans and flavonoids have been isolated from solvent extracts of C. filiformis [6][7][8][9][10]. In contrast, only two papers concerned the volatile components. ...
The essential oils isolated from aerial parts of Cassytha filiformis L. harvested in five locations of Côte d’Ivoire were analyzed by GC(RI), GC-MS and ¹³C-NMR. The oils were dominated by sesquiterpene derivatives and the content of the main components varied substantially from sample to sample: (E)-β-caryophyllene (1.5-34.9%), bicyclogermacrene (1.0-25.8%), α-humulene (0.5-22.0%), spathulenol (1.0-18.5%) and germacrene D (6.6-16.6%). Two compositions could be distinguished: (i) bicyclogermacrene, germacrene D, spathulenol (2/5 samples) and (ii), (E)-β-caryophyllene, α-humulene (3/5 samples).
... Mouse 3T3 fibroblasts, human HeLa and melanoma Mel-5 cell lines were grown in Gibco MEM supplemented with 10 % heat-inactivated foetal-bovine serum and penicillin (100 IU/mL). Cells were incubated in a humidified atmosphere with 5 % CO 2 at 37 °C as previously described (Stévigny C et al., 2002). Stock solution of C. villosa seed-extract was prepared at 10 mg/ml in distilled water. ...
Objective
The present investigation was carried out to evaluate the safety of an aqueous extract of the seeds of Calycotome villosa (Poiret) Link (subsp. intermedia) by determining its cytotoxicity and potential toxicity after acute and sub-chronic administration in rodents.
Materials and Methods
Cytotoxic activity was tested in cancer and non-cancer cell lines HeLa, Mel-5, HL-60 and 3T3. Acute toxicity tests were carried out in mice by a single oral administration of Calycotome seed-extract (0 - 12 g/kg) as well as intraperitoneal doses of 0 - 5 g/kg. Sub-chronic studies were conducted in Wistar rats by administration of oral daily doses for up to 90 days. Changes in body and vital organ weights, mortality, haematology, clinical biochemistry and histologic morphology were evaluated.
Results
The lyophilized aqueous extract of C. villosa exhibited a low cytotoxicity in all cell lines tested with an IC50 > 100 µg/ml. In the acute study in mice, intra-peritoneal administration caused dose-dependent adverse effects and mortality with an LD50 of 4.06 ± 0.01 g/kg. In the chronic tests, neither mortality nor visible signs of lethality was seen in rats. Even AST and ALT were not affected while a significant decrease in serum glucose levels, at 300 and 600 mg/kg was detected. Histopathological examination of the kidney and liver did not show any alteration or inflammation at the end of treatment.
Conclusion
In conclusion, the aqueous extract of C. villosa seed appeared to be non-toxic and did not produce mortality or clinically significant changes in the haematological and biochemical parameters in rats.
... Before in vitro assays, the cytotoxicity of SpE was evaluated as described by Stevigny et al. (2002) to ensure assays were carried out at non-cytotoxic concentrations. The evaluation of cytotoxicity was carried out using the MTT Tetrazolium (3-4,5-dimethylthiazol-2-yl)−2,5 diphenyltetrazolium bromide (Sigma-Aldrich, Saint Louis, MO, USA) colorimetric method that is based on cleavage of the reagent by dehydrogenases in viable cells (Mosmann, 1983). ...
Ethnopharmacological relevance:
Solanum paniculatum L., popularly known as jurubeba, is a common subtropical plant from Brazil, Paraguay, Bolivia, and Argentina, that is used in folk medicine for the treatment of anemia, gastrointestinal disorders and inflammatory conditions in general. In addition to that, an ethnobotanical survey in "Todos os Santos" Bay have pointed out S. paniculatum as an herb to treat asthma. Previous publications have shown that S. paniculatum possesses antibiotic, antioxidant and modulatory effects on gastric acid secretion; however, its anti-inflammatory potential remains unexplored.
Aim of the study:
Herein, we analyzed the hexane extract of S. paniculatum fruits (SpE) for the presence of stigmasterol and β-sitosterol and investigated the anti-inflammatory effect of SpE in vitro.
Materials and methods:
SpE was subjected to high-performance liquid chromatography (HPLC) for standardization and quantification of stigmasterol and β-sitosterol. Spleen cells from BALB/c mice were cultivated and stimulated with pokeweed mitogen and also exposed to 15, 30, and 60µg/mL of SpE. Following treatment, levels of IFN-γ, IL-4, and IL-10 in the culture supernatants were assessed by ELISA. We also evaluated nitric oxide (NO) production by murine LPS-stimulated peritoneal macrophages using the Griess technique. In addition, the ability of SpE to stabilize membranes was assessed using a model of hemolysis induced by heat on murine erythrocytes. Gene expression of Th1-cell-specific Tbx21 transcription factor (T-bet), zinc-finger transcription factor-3 (GATA3), and nuclear factor-κB (NF-κB) in murine spleen cells were assessed by quantitative Polymerase Chain Reaction (qRT-PCR).
Results:
SpE at 15, 30 and 60µg/mL significantly attenuated cell proliferation, decreased IL-4 release, reduced NO production, and improved erythrocyte membrane stabilization in a concentration-dependent manner. SpE was also able to decrease the release of IFN-γ without altering IL-10 levels. The mechanism whereby SpE decreased inflammatory markers may be related to the reduction of NF-κB, T-bet and GATA3 gene expression.
Conclusions:
This study is the first to test the anti-inflammatory action of S. paniculatum. Herein, we provided evidence for the popular use of S. paniculatum in inflammatory conditions. Additional studies must be conducted to further explore the anti-inflammatory potential of SpE and to elucidate possible clinical applications.
... The effects of these compounds are mainly within the cardiovascular system [3,4] . Other activities such as antiparasitic and cytotoxic have also been reported [5,6] . ...
Objective: To study the blood pressure lowering effect of Cassytha filiformis extract in animal models of hypertension and its correlation with the antioxidant activity.
Methods: Male Sprague–Dawley rats were divided into two groups: endocrine hypertension (HTN group) that received a combination of prednisone and salt for two weeks and oxidative stress-associated hypertension (HTN-OS group) that received additional induction of l-Nitro Arginine Methyl Esther (l-NAME) for two days. Each group was subdivided into 4 and treated intravenously with the extract 5; 10; and 20 mg/kg, and vehicle control. The systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were recorded. The blood was taken before and at the end of recording for the measurement of serum concentration of nitric oxide (NO). The changes of blood pressure were analyzed by two-way ANOVA while its correlation with NO concentration was analyzed by Pearson's Correlation.
Results: The study showed a significant antihypertensive effect of the extract as compared with control group (P 0.05).
Conclusions: The study concludes that C. filiformis extract in the dose of 5 mg/kg exhibits the best blood pressure lowering effect in both animal models. Antihypertensive activity of the extract is not correlated with its antioxidant effect.
... The Antitrypanosomal activity, toxicity test, and cytotoxicity assay were done according to Räz et al. [6], Sleet and Brendel [7] and Stevigny et al. [8], respectively. ...
... The Antitrypanosomal activity, toxicity test, and cytotoxicity assay were done according to Räz et al. [6], Sleet and Brendel [7] and Stevigny et al. [8], respectively . 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 Uncited references [1][2][3][4][5]. ...
This article reports data on four carbazones of piperitone: semicarbazone 1, thiosemicarbazone 2, 4-phenyl semicarbazone 3 and 4-phenyl thiosemicarbazone 4 prepared directly in situ from essential oil of Cymbopogon schoenantus, whose GC-FID and GC–MS analysis revealed piperitone as major component (68.20%). The structures of hemi-synthesized compounds were confirmed by high throughput IR, MS, ¹H and ¹³C NMR based spectrometric analysis. Their antiparasitic activities were evaluated in vitro on Trypanosoma brucei brucei (Tbb). The compound 3 (IC50=8.63±0.81 µM) and 4 (IC50=10.90±2.52 µM) exhibited antitrypanosomal activity, 2 had a moderate activity (IC50=74.58±4.44 µM) but 1 was void of significant activity (IC50=478.47 µM). The in vitro tests showed that all compounds were less cytotoxic against the human non cancer fibroblast cell line (WI38) (IC50>80 µM) while only 2 (IC50=21.16±1.37 μM) and 4 (IC50=32.22±1.66 µM) were cytotoxic against the Chinese Hamster Ovary (CHO) cells and toxic on Artemia salina (Leach) larvae. Piperitone 4-phenyl semicarbazone 3, the best antitrypanosomal compound, showed also a selectivity index (SI) higher than 7 on the larvae and the tested cells and therefore might be further studied as antitrypanosomal agent. Also, all compounds except 3 showed selectivity between the two tested cell lines (SI>2). This data reveals for the first time the antitrypinosomal properties of thiosemicarbazones, their cytotoxicity on mammalian cells as well as their activities against Tbb and A. salina Leach.
... In order to explore more new and bioactive constituents from I. aromatica, a detailed phytochemical investigation on the tubers of I. aromatica was carried out in the present study. Three new monoterpene phenylpropionic acid esters, illigerates A-C (1-3), and one new aporphine alkaloid, illigeranine (4), as well as four known ones, actinodaphnine (5) (Stevigny et al. 2002;Lee et al. 2007), nordicentrine (6) (Likhitwitayawuid et al. 1993), 8-hydroxycavacrol (7) (Kulkarni and Joshi 2013), and 3-hydroxy-a,4-dimethyl styrene (8) (Patwardhan and Gupta 1983) (Fig. 1), were isolated and identified by HRESIMS, 1D and 2D NMR, Electronic supplementary material The online version of this article (doi:10.1007/s12272-016-0860-3) contains supplementary material, which is available to authorized users. and electronic circular dichroism (ECD) spectra. ...
Three new monoterpene phenylpropionic acid esters, illigerates A-C (1-3), and one new aporphine alkaloid, illigeranine (4), as well as four known ones, actinodaphnine (5), nordicentrine (6), 8-hydroxy carvacrol (7), and 3-hydroxy-α,4-dimethyl styrene (8), were isolated from the tubers of Illigera aromatica. The structures of 1-4 were identified by HRESIMS, 1D and 2D NMR, and electronic circular dichroism spectra. Compound 1 potently inhibited NO production in LPS-stimulated RAW264.7 cells with an IC50 value of 18.71 ± 0.85 μM; compound 1, 3, and 4 showed moderate butyrylcholinesterase inhibitory activities with the IC50 values of 46.86 ± 0.65, 53.51 ± 0.71, and 31.62 ± 1.15 μM, respectively. Compound 4 showed weak AChE inhibitory activity with an IC50 value of 81.69 ± 2.07 μM, and compounds 5 and 6 possessed moderate AChE inhibitory activities with the IC50 values of 47.74 ± 1.66 and 40.28 ± 2.73 μM, respectively. This paper provides a chemical structure and bioactive foundation for using I. aromatica as an herbal medicine.
... The presence of dicentrine and neolitsine may support the use of the plant as an antihypertensive, but standardisation is necessary as it seems that the alkaloid concentration may be highly variable; such a quality control method has recently been described [14]. However, the total safety of the use of the plant is uncertain because dicentrine and neolitsine were shown to be cytotoxic [15][16][17], and so further toxicological studies are needed. ...
Spirospermum penduliflorum Thouars (Menispermaceae) is widely used on the eastern coast of Madagascar to treat hypertension. The aim of the present study was to analyse the vasorelaxant properties of different leaf extracts. The activity of the n-hexane, dichloromethane and methanolic extracts was tested on phenylephrine-contracted aorta. The dichloromethane extract was shown to be the most effective. Further fractionation of this extract led to the isolation of an active fraction relaxing phenylephrine-contracted aorta with an IC50 of 0.18 μg/mL {log IC50 (μg/mL) -0.74 ± 0.03} but was much less effective on KCl induced contractions. Bioassay-guided fractionation of this fraction led to the isolation of two aporphinoid alkaloids, neolitsine and dicentrine, which at concentrations of 0.1 μM and 1 μM displaced to the right the phenylephrine concentration-contraction curve. Our results show that Spirospermum penduliflorum extracts possess vasorelaxant activity in vitro that could be related to the presence of dicentrine in the extracts having an a1 antagonist activity. This finding is not in accord with the previous studies by Rasoanaivo et al. where no alkaloids were detected in the leaves of Spirospermum penduliflorum. Keywords: Spirospermum penduliflorum, Menispermaceae, Aporphine alkaloids, Antihypertensive activity.
... However, this extract showed a quite high cytotoxicity with IC 50 of 10.10 ± 0.20 and 4.82 ± 0.67 mg/L on the WI38 and J774 cell lines. Further studies are needed to determine whether indirect antimicrobial activity and cytotoxicity are due to the same compounds but aporphine alkaloids could be responsible for the observed cytotoxicity (Stévigny et al. 2002). ...
In a world of increasing resistance to current antibiotics, search of novel therapeutic options is urgently needed. The aim of this work was to screen plant crude extracts for direct or indirect (inhibition of resistance) antimicrobial activity. Four crude extracts from 12 plants traditionally used in Africa for the treatment of infections were obtained by successive extraction with hexane, dichloromethane, ethyl acetate, and methanol. All extracts were tested against Staphylococcus aureus MRSA ATCC33591 [resistant to β-lactams by production of β-lactamases and of a modified PBP target (PBP2a)]. Direct antimicrobial activity was tested by determination of Minimal Inhibitory Concentrations (MIC), and indirect activity, by determining interactions between antibiotics and extracts using checkerboard titration and calculation of Fractional Inhibitory Concentration Index (FICI; synergy: FICI ≤ 0.5; additivity: FICI ≤ 1). Combined antibiotics were ampicillin (sensitive to resistance mediated by β-lactamases and PBP2a) and oxacillin (sensitive to resistance mediated by PBP2a only). The dichloromethane extract of Vitellaria paradoxa leaves, the methanol extracts of Vitellaria paradoxa, Cola gigantea leaves and twigs, and of Tapinanthus bangwensis aerial parts showed direct antimicrobial activity (MIC 250–500 mg/L). The methanol extracts of Vitellaria paradoxa and Cola
gigantea leaves and twigs showed additive or synergistic effects with oxacillin and ampicillin on MRSA ATCC33591 (FICI 0.28–1), suggesting a possible inhibition of PBP2a. The methanol extract of Tapinanthus bangwensis aerial parts and Anchomanes difformis roots improved the activity of ampicillin only (FICI 0.38–1), suggesting β-lactamase inhibition. Polyphenols and particularly tannins were shown to be responsible for these last effects, at least partially for Vitellaria paradoxa. These data need further research aiming at identifying the active compounds in these extracts.
... The cytotoxicity of compounds on WI38 cells was evaluated as described by Stevigny et al. [31], in 96-well microtiter plates, using the tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (Sigma)) colorimetric method based on the cleavage of the reagent by mitochondrial dehydrogenases in viable cells [32]. Camptothecin was used as positive cytotoxic reference compound. ...
In this work, a series of hybrid compounds were tested as antiparasitic substances. These hybrids were prepared from bile acids and a series of antiparasitic Cinchona alkaloids by the formation of a covalent C-C bond via a decarboxylative Barton-Zard reaction between the two entities. The bile acids showed only weak antiparasitic properties, but all the hybrids exhibited high in vitro activities (IC50: 0.48-5.39 μM) against Trypanosoma brucei. These hybrids were more active than their respective parent alkaloids (up to a 135 fold increase in activity), and displayed good selectivity indices. Aditionally, all these compounds inhibited the in vitro growth of a chloroquine-sensitive strain of Plasmodium falciparum (3D7: IC50: 36.1 nM to 8.72 μM), and the most active hybrids had IC50s comparable to that of artemisinin (IC50: 36 nM). Some structure-activity relationships among the group of 48 hybrids are discussed. The increase in antiparasitic activity may be explained by an improvement in bioavailability, since the more lipophilic derivatives showed the lowest IC50s.
Copyright © 2015. Published by Elsevier Masson SAS.
... After this period of incubation, cell viability was assessed using the tetrazolium salt (MTT, WST-1 or NBT) colorimetric method based on the cleavage of the reagent to formazan dye by mitochondrial dehydrogenase in viable cells (Mosmann, 1983). The absorbance was measured at 450 nm (or 540-560 nm) with a scanning multiwell spectrophotometer and the percentage of cytotoxicity calculated (Kuypers et al., 2006;Stevigny et al., 2002). ...
Ethnopharmacological relevance:
Malaria is the most prevalent parasitic disease and the foremost cause of morbidity and mortality in the Democratic Republic of Congo. For the management of this disease, a large Congolese population recourses to traditional medicinal plants. To date the efficacy and safety of many of these plants have been validated scientifically in rodent malaria models. In order to generate scientific evidence of traditional remedies used in the Democratic Republic of Congo for the management of malaria, and show the potential of Congolese plants as a major source of antimalarial drugs, this review highlights the antiplasmodial and toxicological properties of the Congolese antimalarial plants investigated during the period of 1999-2014. In doing so, a useful resource for further complementary investigations is presented. Furthermore, this review may pave the way for the research and development of several available and affordable antimalarial phytomedicines.
Materials and methods:
In order to get information on the different studies, a Google Scholar and PubMed literature search was performed using keywords (malaria, Congolese, medicinal plants, antiplasmodial/antimalarial activity, and toxicity). Data from non-indexed journals, Master and Doctoral dissertations were also collected.
Results:
Approximately 120 extracts and fractions obtained from Congolese medicinal plants showed pronounced or good antiplasmodial activity. A number of compounds with interesting antiplasmodial properties were also isolated and identified. Some of these compounds constituted new scaffolds for the synthesis of promising antimalarial drugs. Interestingly, most of these extracts and compounds possessed high selective activity against Plasmodium parasites compared to mammalian cells. The efficacy and safety of several plant-derived products was confirmed in mice, and a good correlation was observed between in vitro and in vivo antimalarial activity. The formulation of several plant-derived products also led to some clinical trials and license of three plant-derived drugs (Manalaria(®), Nsansiphos(®), and Quinine Pharmakina(®)).
Conclusion:
The obtained results partly justify and support the use of various medicinal plants to treat malaria in folk medicine in the Democratic Republic of Congo. Antimalarial plants used in Congolese traditional medicine represent an important source for the discovery and development of new antimalarial agents. However, in order to ensure the integration of a larger number of plant-derived products in the Congolese healthcare system, some parameters and trends should be considered in further researches, in agreement with the objectives of the "Traditional Medicine Strategy" proposed by the World Health Organization in 2013. These include evaluation of geographical and seasonal variation, investigation of reproductive biology, assessment of prophylactic antimalarial activity, evaluation of natural products as adjuvant antioxidant therapy for malaria, development of plant-based combination therapies and monitoring of herbal medicines in pharmacovigilance systems.
... It has also shown to attenuate catecholamine oxidation-induced brain mitochondrial dysfunction [17]. Aporphinoids in general exhibit a wide range of biological properties [18,19], for example isolated aporphines of plant Cassytha filiformis (Lauraceae) possess in vitro antiproliferative properties in a number of cancer and non-cancer cell lines [20,21]. Several of the aporphine alkaloids extracted from natural herbs and related derivatives of boldine are known as inhibitors of topoisomerase I or II [22]. ...
... This compound has shown to attenuate brain mitochondrial dysfunction induced by catecholamine oxidation [12]. Aporphine alkaloids in general exhibit a wide range of biological activities such as antiproliferative properties in a number of cancer and non-cancer cell lines [13] and inhibition of topoisomerase I or II [14]. This study was focused on an evaluation of the cytotoxicity and antiproliferative effect of this compound with special reference to telomerase inhibition and induction of apoptosis. ...
Plant metabolites are valuable sources of novel therapeutic compounds. In an anti-telomerase screening study of plant secondary metabolites, the aporphine alkaloid boldine (1,10-dimethoxy-2,9-dihydroxyaporphine) exhibited a dose and time dependent cytotoxicity against hepatocarcinoma HepG-2 cells. Here we focus on the modes and mechanisms of the growth-limiting effects of this compound. Telomerase activity and expression level of some related genes were estimated by real-time PCR. Modes of cell death also were examined by microscopic inspection, staining methods and by evaluating the expression level of some critically relevant genes. The growth inhibition was correlated with down-regulation of the catalytic subunit of telomerase (hTERT) gene (p < 0.01) and the corresponding reduction of telomerase activity in sub-cytotoxic concentrations of boldine (p < 0.002). However, various modes of cell death were stimulated, depending on the concentration of boldine. Very low concentrations of boldine over a few passages resulted in an accumulation of senescent cells so that HepG-2 cells lost their immortality. Moreover, boldine induced apoptosis concomitantly with increasing the expression of bax/bcl2 (p < 0.02) and p21 (p < 0.01) genes. Boldine might thus be an interesting candidate as a potential natural compound that suppresses telomerase activity in non-toxic concentrations.
Purpose
Lichens are well-known as a source of pharmacologically active compounds. This includes anticancer compounds which have biomass constraints including using traditional techniques of lichen bioprospecting. This current study reports the use of cutting-edge metabolomics and a computational approach to discover anticancer biomarkers from Indonesian lichens.
Methods
Seven lichen crude extracts were evaluated against cervical cell lines HeLa using a MTT assay and secondary metabolites were profiled and recorded via a gas chromatography-mass spectrometry (GC-MS) protocol. A multivariate analysis orthogonal partial least-squares-discriminant analysis (OPLS-DA) was employed to determine anticancer biomarker of the lichens. A structure-based computational study against the HeLa cancer cell related protein targets (BCL-2 (4MAN), AKT-1 (4GV1), MCL-1 (5FDO), and BRAF (5VAM)) was used to determine the most potent biomarker.
Results
The MTT assessment indicated the seven lichens possessed strong, medium and weak cytotoxicity. Multivariate analysis showed an OPLS-DA score plot with distinct separation among the strong, medium and weak cytotoxic groups. The biplot OPLS-DA and GC-MS analysis proposed 13 compounds of Parmelia caroliniana and 12 compounds of Physcia cf. millegrana as anticancer biomarker candidates. Docking experiments revealed 6-amino-3,4,7-triphenylpyrido[2’,3’:4,5]thieno[2,3-c]pyridazine 4 from P. caroliniana to possess the highest binding affinity against BCL-2 (4MAN), AKT-1 (4GV1), MCL-1 (5FDO), and BRAF (5VAM) proteins with affinity energy values of -10.0, -11.6, -10.4, -12.6, respectively.
Conclusion
The study successfully revealed compound 4 as the anticancer biomarker against HeLa cell cancer of P. caroliniana in which can be further explored through in vitro and in vivo studies. Further, the metabolomic protocol established can be adapted as a tool for biomarker discoveries from other medicinal plants.
Backgrounds
Plants have always been an important source of food and drugs, in addition to their application in medical and cosmetic sectors. The popularity of herbal remedies has increased in many countries in recent decades. Herbal medicines contain numerous active phytocomponents with different biological activities. Alkaloid class phytochemicals have diverse chemical structures and pharmacological activities in nature. Additionally, Aporphinoids are an important class of plant secondary metabolites that have been used for the treatment of numerous human disorders for a long time in traditional medicine. Dicentrine is an aporphine class phytochemical isolated from numerous medicinal plants, including Actinodaphne sesquipedalis and Lindera megaphylla.
Methods
The biological potential of dicentrine, an aporphine alkaloid derivative, has been described in the present work. Scientific data on dicentrine were collected here from different scientific databases and presented in this paper in order to know the biological importance of dicentrine in medicine for the treatment of human complications. Further, detailed pharmacological activities and scientific data on dicentrine were also analyzed in order to determine its therapeutic potential in medicine. Moreover, its analytical aspects were also described in this work to understand its separation and isolation methods.
Results
The present work described the biological potential of dicentrine in medicine and its analytical aspects. It signified the biological potential of dicentrine in cancer, breast cancer, oral squamous cell carcinoma, lung adenocarcinoma, blood pressure, inflammatory disorders, hyperlipidaemia, arrhythmia, stomach muscle, and glomerulonephropathy. Further, its effectiveness in medicine was found to be mainly because of its antiplatelet, alpha 1-adrenoceptor, epidermal growth factor, antiprotozoal, larvicidal, antimicrobial, topoisomerase II, and acetylcholinesterase inhibitory potential. Moreover, other scientific data also signified its metabolism and pharmacokinetic parameters in terms of its analytical aspects in medicine.
Conclusion
The present review gives us an updated summary of the scientific information for pharmacological activities and analytical aspects of dicentrine in medicine. It also signified the potential contribution of dicentrine in medicine for the development of a newer class of drug molecules for human disorders.
Covering literature to December 2022This review provides a comprehensive account of all natural products (500 compounds, including 17 semi-synthetic derivatives) described in the primary literature up to December 2022, reported to be capable of inhibiting the egg hatching, motility, larval development and/or the survival of helminths (i.e., nematodes, flukes and tapeworms). These parasitic worms infect and compromise the health and welfare, productivity and lives of commercial livestock (i.e., sheep, cattle, horses, pigs, poultry and fish), companion animals (i.e., dogs and cats) and other high value, endangered and/or exotic animals. Attention is given to chemical structures, as well as source organisms and anthelmintic properties, including the nature of bioassay target species, in vivo animal hosts, and measures of potency.
This datasheet on Cassytha filiformis covers Identity, Overview, Distribution, Dispersal, Hosts/Species Affected, Diagnosis, Biology & Ecology, Environmental Requirements, Natural Enemies, Impacts, Uses, Prevention/Control, Further Information.
This study involves aporphine alkaloids identified through ¹³C Nuclear Magnetic Resonance (NMR) spectroscopic data. For the present publication, articles were selected from several databases on aporphine alkaloids from 1994 to 2021. In this class, more than 700 compounds have been registered, with 221 were included in this section, among which 122 were characterized for the first time in the investigated period. The study also addresses their biosynthetic pathways, classifying substances according to their structural characteristics based on established literature. Furthermore, pharmacological activities related to the aporphine alkaloids highlighted in this section are also presented, giving an overview of the various applications of these compounds.
Historically, plants with a wide range of natural products they possess have long served as important sources of therapeutical agents. Unfortunately, progress in the construction of synthetic chemical libraries shifted the trend from natural products. With rising resistance to available antibacterial and antifungal agents, natural products are now regaining their attention. They represent an ideal platform for antimicrobial drug discovery, due to their structural complexity, functional group density, and the evolved ability to penetrate the bacterial cell envelope. Plant alkaloids are among these natural products with novel structures and significant bioactivities. Following a detailed comparative analysis of the reported antimicrobial activities of the alkaloids derived from benzyltetrahydroisoquinoline alkaloids of two closely related plant families: Papaveraceae and Fumariaceae, we specifically focus on some structural aspects of antimicrobial activities of these alkaloids. Overall, tetrahydroprotoberberines are commonly weaker agents than their corresponding protoberberines. While methylation enhances activity, the reduction of a molecule results in activity loss. Furthermore, alkaloid charge could be an important issue in enhancing the interactions with the membranes. Our findings indicated that although a large number of studies focus on antimicrobial activities is huge, the number of microorganisms tested is highly variable. The generalizations can be poor if the strains tested are different.
Leaves of Vitellaria paradoxa, also called “Shea butter tree”, are used in traditional medicine to treat various symptoms including malaria fever, dysentery, or skin infections. Composition of the dichloromethane extract of V. paradoxa leaves possessing antiparasitic activities was investigated. Five pentacyclic triterpenic acids together with 6 ester derivatives were isolated and identified by standards comparison, MS and 1H-NMR analysis. Corosolic, maslinic, and tormentic coumaroyl esters and their corresponding triterpenic acids were isolated from this plant for the first time. The antiparasitic activities of the 11 isolated compounds were evaluated in vitro on Plasmodium falciparum, Trypanosoma brucei brucei, and Leishmania mexicana mexicana and their selectivity determined by cytotoxicity evaluation on WI38 cells. None of the isolated compounds showed good antiplasmodial activity. The antitrypanosomal activity of individual compounds was in general higher than their antileishmanial one. One isolated triterpenic ester mixture in equilibrium, 3-O-p-E/Z-coumaroyltormentic acids, showed an attractive promising antitrypanosomal activity (IC50 = 0.7 µM) with low cytotoxicity (IC50= 44.5 µM) compared to the corresponding acid. Acute toxicity test on this ester did not show any toxicity at the maximal cumulative dose of 100 mg/kg intraperitoneally on mice. In vivo efficacy evaluation of this compound, at 50 mg/kg by intraperitoneal route on a T. b. brucei-infected mice model, showed a significant parasitemia reduction on day 4 post-infection together with 33.3% survival improvement. Further bioavailability and PK studies are needed along with mode of action investigations to further assess the potential of this molecule.
This is an extensive review on epiphytic plants that have been used traditionally as medicines. It provides information on 185 epiphytes and their traditional medicinal uses, regions where Indigenous people use the plants, parts of the plants used as medicines and their preparation, and their reported phytochemical properties and pharmacological properties aligned with their traditional uses. These epiphytic medicinal plants are able to produce a range of secondary metabolites, including alkaloids, and a total of 842 phytochemicals have been identified to date. As many as 71 epiphytic medicinal plants were studied for their biological activities, showing promising pharmacological activities, including as anti-inflammatory, antimicrobial, and anticancer agents. There are several species that were not investigated for their activities and are worthy of exploration. These epipythes have the potential to furnish drug lead compounds, especially for treating cancers, and thus warrant indepth investigations.
A new dibenzopyrrocoline alkaloid, (-)-grandifloramine (1), together with five known ones, actinodaphnine (2), N-methyllaurotetanine (3), boldine (4), lindcarpine (5), and (+)-norboldine (6), were isolated from Illigera grandiflora W. W. Sm. et J. F. Jeff. The structure of 1 was identified by HRESIMS, 1D/2D NMR, and electronic circular dichroism (ECD) spectra. Compound 1 and 2 exhibited the moderate inhibitory activity against acetylcholinesterase and 3 showed moderate butyrylcholinesterase inhibitory activity. This is the first report of the chemical constituents of I. grandiflora.
Illigera henryi, an endemic traditional Chinese medicine, contains abundant aporphine alkaloids that possess various bioactivities. In the present study, tubers of I. henryi were fermented by several fungi, and the acetylcholinesterase (AChE) inhibitory activities of non-fermented and fermented I. henryi were measured. The results showed that the fermentation of I. henryi with Clonostachys rogersoniana 828H2 is effective for improving the AChE inhibitory activity. A key biotransformation was found during the C. rogersoniana fermentation for clarifying the improvement of the AChE inhibitory activity of I. henryi: (S)-actinodaphnine (1) was converted to a new 4-hydroxyaporphine alkaloid (4R,6aS)-4-hydroxyactinodaphnine (2) that possessed a stronger AChE inhibitory activity, with an IC50 value of 17.66 ± 0.06 μM. This paper is the first to report that the pure strain fermentation processing of I. henryi and indicated C. rogersoniana fermentation might be a potential processing method for I. henryi.
Two new long-chain secobutanolides, illigerones A (1) and B (2), together with five known compounds, actinodaphnine (3), cryptodorine (4), β-sitosterol (5), daucosterol (6), and stigmasterol (7) were isolated from Illigera henryi W. W. Sm. The structures of 1 and 2 were identified by HRESIMS, EIMS, 1D/2D NMR, and electronic circular dichroism (ECD) spectra. Compound 1 exhibited the moderate cytotoxic activities against five tumour cells. This is the first report of secobutanolides isolated from plants of Hernandiaceae.
As a kind of common compositions in plants, there are many researches about alkaloids, which was firstly found from Nelumbo nucifera. Now more and more aporphine alkaloids appear during the experiments, which belong to isoquinoline type. There are number of pesticide effects about them, which have been revealed in recent years. So comprehensive information about the locality, formation and pesticide effects have been studied and presented in this research in different botany about aporphine alkaloids.
Alkaloids - Secrets of Life: Alkaloid Chemistry, Biological Significance, Applications and Ecological Role, Second Edition provides knowledge on structural typology, biosynthesis and metabolism in relation to recent research work on alkaloids, considering an organic chemistry approach to alkaloids using biological and ecological explanation. The book approaches several questions and unresearched areas that persist in this field of research. It provides a beneficial text for academics, professionals or anyone who is interested in the fascinating subject of alkaloids. Each chapter features an abstract. Appendices, a listing of alkaloids, and plants containing alkaloids are all included, as are basic protocols of alkaloid analysis.
The interaction in populations or between populations, in reality, is the interaction of individuals and the interaction of the life activities, energy, and behavior of chemical molecules. Alkaloids are chemical instruments of many organisms in the biological community for their vitality, defense, adaptations, competition get resiliency in life. Alkaloids occur in aquatic and terrestrial ecosystems, in different climates and zones. They apparently strengthen the organism’s ability to survive. Alkaloids are molecules in some invasive species, although alkaloids occur in local flora and fauna, and they are characteristic molecules for endemic organisms. Alkaloids are a special group of secondary compounds and are part of an organism’s adaptation to its living environment. They are not toxic when stored but become toxic as a result of cell pH change. The defensive function of alkaloids is only secondary and connected to the internal immune and regulation processes. Animal responses to alkaloids are very diverse. Some animals can tolerate alkaloids relatively well, while others are harmed or even poisoned by them. Animal behavior in relation to alkaloids can be different and depends on historical evolutionary and coevolutionary factors. Sequestration of alkaloids by animals is connected with these processes. Alkaloids are a part of plant-derived nutrition. The selective toxicity of these compounds in vertebrates is clearly observed. Vertebrates have the capacity to recognize alkaloids. Alkaloids take part in the life processes of some invertebrates as pheromones, inducers of sexual behavior, and in reproduction.
In this study, we have tested alcoholic extracts (60%) from four Beninese plants: Ocimum gratissimum L.,
Acanthospermum hispidum DC, Caesalpinia bonduc (L) Roxb and Calotropis procera W. T. Aiton. They are
used by the healers to prevent opportunistic diseases associated to HIV-AIDS; on six strains such as: Escherichia
coli O 157H7, Staphylococcus aureus ATCC 25923 which resist to methicillin (MRSA), Salmonella typhi,
Klebsiella pneumonia, Candida albicans ATCC 10231, and Mycobacterium bovis BCG 040812 which cause
microbial infections associated with HIV-AIDS. The results show that all the extracts are bacteriostatic and
fungistatic but only the hydro-ethanolic extracts of Acanthospermum hispidum (HE2) and of Caesalpinia bonduc
(HE3) presented antibiotic power (respectively ap = 2 and ap = 4) on Candida albicans ATCC 10231. The
Mycobacterium bovis BCG shown resistance to tested extracts (CMI > 250 μg/mL). The two fungicidal extracts
HE2 and HE3 did not show harmful effects on the cells WI–38 with an IC50 > 100 μg/mL for HE2 and IC50 = 50
μg/mL for HE3. The successive bio-guided purifications of extracts HE2 and HE3 permitted isolation of three
antibacterial compounds: Flavanone (M1); stigmasterol (M2); and quercetin (M3). The three isolated compounds
possess antibiotic power (ap 3±1) on tested strains and are not toxic on shrimp larvae (LC50: 0.30 ± 0.17 mg/mL).
Alteration of gene transcription is one of the approaches to control the expression of selected genes and could be achieved by molecules acting on the interactions between transcription factors and DNA. In this respect, DNA-binding drugs are of great interest and object of a large number of research articles. The most suitable techniques for a fast screening are the electrophoretic mobility shift assay and the filter binding approach. In this communication, we present evidence showing that extracts from medicinal plants could exhibit the ability to inhibit the interactions between nuclear factors and the specific DNA elements. Among the results obtained, we found low concentrations of Emblica officinalis, Vernonia anthelmintica, Terminalia arjuna and Rumex maritimus, and very low concentrations of Saraca asoka extracts inhibit NF-kB/DNA interactions. On the contrary, high amounts of extracts from Argemone mexicana were still unable to inhibit NF-kB/DNA interactions. The employment of several analytical and preparative procedures, among which preparative and analytic high-performance liquid chromatography (HPLC), liquid-chromatography/mass-spectrometry (LC/MS) and gas-chromatography/mass-spectrometry (GC/MS), will help in identifying the bioactive compounds responsible for this very interesting feature.
Cassytha filiformis alcohol decoction is used by traditional healers in Idem-Ogwa, Mbaitoli Local Government Area of Imo State, Nigeria, in the treatment of liver disorders ranging from hepatitis to susceptive poisoning and alcohol intoxication. The methanol extract of the aerial parts of Cassytha filiformis L. was investigated for hepatoprotective activity in rats challenged with carbon tetrachloride (CCl4). Apart from group 1 (normal), all other groups were pre-challenged with a single intraperitoneal injection of 0.7 ml of 20 % (v/v) CCl4 solution in olive oil. Group 2 (negative control) was given distilled water (10 ml kg−1, p.o.). Group 3 were treated with silymarin (35 mg kg−1 p.o.). Groups 4, 5, and 6 received oral treatments of 75, 150, and 300 mg kg−1 of the extract of C. filiformis respectively. All treatments were given by stomach intubation and at 12 h intervals for 7 days. Sodium pentobarbitone-induced sleeping time assay was carried out on the animals at 12 h after the last treatment on day 7 by intraperitoneal administration of Na-pentobarbitone (35 mg kg−1). Serum from individual animal was used to determine the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, total protein and in vitro red blood cell membrane stability. The extract was safe up to 2000 mg kg−1 orally and did not induce overt clinical manifestation or death in rats. The extract significantly (p
Cassythine, C19H19N05, the major phenolic alkaloid of Cassytha filiformis L., is a new aporphine. Its NO-dimethyl derivative has been identified as the known alkaloid (+)-ocoteine (11), and from spectroscopic data cassythine is considered to be (Ia). A new non-phenolic base, cassythidine, C19H17NO5, is considered to be(IV).
The major alkaloid of Cassytha melantha R.Br, and Cassytha glabella R.Br. is (+)-9-hydroxy-10-methoxy-1,2-methylenedioxyaporphine (cassythicine), which has not been previously found to occur naturally, although the (±)-form has been synthesized by Tomita and Kikkawa. A minor alkaloid from C. melantha, isolated only in the form of an NO- diacetyl derivative, appears to be the noraporphine corresponding to cassythicine and it is presumably identical with the known alkaloid actinodaphnine. A study has been made of the N.M.R. spectra of a number of N- acetyl-N-methylaminoethylphenanthrenes, obtained from aporphines by heating with acetic anhydride. These show not only the expected splitting of the N-methyl and N-acetyl signals due to cis-trans isomerism of the amide group, but also a long-range splitting of the signals from certain aryl protons.
Thirteen alkaloids have been isolated from Brazilian Cassytha americana (C. filiformis L., Lauraceae). The structures of 1,2,9,10-bismethylenedioxy-3-methoxydibenzo[de,g]quinolin-7-one and 1,2,9,10-bismethylenedioxy-dibenzo[de,g]quinolin-7-one are suggested for the new oxoaporphine bases cassamedine and cassameridine. The plant also yielded ten previously known aporphine bases.
The circular dichroism (cd) spectra of nineteen aporphines of widely differing substitution patterns have been examined between 200 and 400 nm. Three major cd band systems exist, in the 220, 270-280, and 300 nm region. Two intense oppositely-signed Cotton effects (CE's) between 200 and 250 nm are substitution-independent and configuration-dependent, as is the third CE at 270-283 nm. In the region 293-327 nm, there are two further CE's which are substitution-dependent. In the case of symmetrically (1,2,10,11) substituted aporphines, the bands in the 300 nm region are split into two oppositely-signed CE's with a pattern similar to that observed for the 220 nm region.
Bioassay-directed fractionation from the methanol extract of the fresh herb of Cassytha filiformis led to the isolation and characterization of six aporphinoid alkaloids, actinodaphnine (1), N-methylactinodaphnine (2), cathafiline (3), cathaformine (4), predicentrine (5) and ocoteine (6). They showed potent inhibitory activity of rabbit platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid (AA), collagen and platelet-activating factor (PAF) factor. Alkaloids 1 and 2 also exhibited strong inhibition of aortic contraction induced by K+ (80 mM) and norepinephrine (3 μM). Moreover, 3 and 4 are two novel aporphinoid alkaloids possessing an N-(methoxycarbonyl) group. © 1998 John Wiley & Sons, Ltd.
A screening test of antimicrobial activities for some of the isoquinoline alkaloids and their first and second Hofmann elimination products was conducted in this study. Results showed that (+)-actinodaphnine (1), (+)-N-Me-actinodaphnine (2), (+)-anonaine (17), (-)-xylopine (19) and (-)-N-Me-xylopine MeI (20), had the strongest inhibitory activities against three G(+) bacteria (Bacillus cereus, Micrococcus sp. and Staphylococcus aureus) MIC greater than or equal to 50 micrograms/ml). Whereas anhydroushinsunine (34), anhydroushinsunine MeI (35), ushinsunine isomethine (38), dicentrine methine (23), roemerine methine (26), dicentrine bismethine (29) and O-Me-armepavine methine (48) also had antibacterial effects against these same three G(+) bacteria (MIC = 50-300 micrograms/ml). However, only (+)-actinodaphnine (1) and roemerine methine (26) showed weak effects against two G(-) bacteria (Escherichia coli and Klebsiella pneumonia) (MIC = 300 micrograms/ml). (+)-Actinodaphnine(1), (+)-N-Me-actinodaphnine (2), (+)-anonaine (17), anhydroushinsunine (34), anhydroushinsunine MeI (35), ushinsunine isomethine (38), O-Me-armepavine methine (48) and O,O-di-Et-N-Me-coclaurine methine (49) had potent antifungal activities against Candida albicans, Cryptococcus neoformans and other Candida species (MIC = 62.5-1000 micrograms/ml).
A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
We evaluated, in cell cultures, the action of a series of 19 aporphine alkaloids against Herpes simplex virus type 1 (HSV-1). On the basis of viral titre reduction, six alkaloids were found to be active. The mode of action of the three most potent inhibitors, oliverine HCl, pachystaudine, and oxostephanine, was studied. These compounds did not have any virucidal or prophylactic effect but they were shown to interfere with the viral replicative cycle. Although DNA synthesis was reduced, their exact target remains to be elucidated. In the discussion, some structure-activity relationships are considered.
d-Dicentrine, a naturally occurring aporphine type isoquinoline alkaloid, isolated from the root of Lindera megaphylla Hemsl. (Lauraceae), was evaluated for its potential anti-cancer activity. We found d-dicentrine significantly inhibited the growth of human hepatoma cell line HuH-7 by delaying its doubling time in tissue culture. An in vitro colony forming assay showed that d-dicentrine decreased the colony formation efficiency in both hepatoma cell lines, HuH-7 and MS-G2, used in our study. Biosyntheses of the macromolecules DNA and RNA were also strongly inhibited. An MTT assay in 21 tumor cell lines also revealed that d-dicentrine was most cytotoxic to esophageal carcinoma HCE-6, lymphoma cell lines Molt-4 and CESS, leukemia cell lines HL60 and K562, and hepatoma cell line MS-G2. An in vitro tumor growing assay in the Severe Combined immunodeficiency (SCID) mice showed that intraperitoneal injection of d-dicentrine at the dose of 100 micrograms twice a week for 4 weeks significantly inhibited the tumor incidence of leukemia cell line K562 in SCID mice. All these data indicated that d-dicentrine has potential anti-tumor applications.
Using a bioassay-directed fractionation method, three new compounds, including an aporphine alkaloid, cassyformine (4); an oxoaporphine alkaloid, filiformine (8), and a lignan, (+)-diasyringaresinol (10), along with 14 known compounds, were further isolated and characterized from the MeOH extract of the fresh herbs of Cassytha filiformis. Among the isolates of this plant, cathafiline (1), cathaformine (2), actinodaphnine (3), N-methylactinodaphnine (5), predicentrine (6), and ocoteine (7) exhibited significant antiplatelet aggregation activity.
The aporphine alkaloids (+)-dicentrine and (+)-bulbocapnine are non-planar molecules lacking features normally associated with DNA binding by intercalation or minor groove binding. Surprisingly, dicentrine showed significant activity as a topoisomerase II (EC 5.99.1.3) inhibitor and also was active in a DNA unwinding assay. The DNA unwinding suggests DNA intercalation, which could explain the inhibition of topoisomerase II. Bulbocapnine, which differs from dicentrine only by the presence of a hydroxyl group at position 11 and the absence of a methoxyl group at position 9, was inactive in all assays. Molecular modeling showed that dicentrine can attain a relatively planar conformation, whereas bulbocapnine cannot, due to steric interaction between the 11-hydroxyl group and an oxygen of the methylenedioxy ring. These observations suggest that dicentrine is an "adaptive" DNA intercalator, which can bind DNA only by adopting a somewhat strained planar conformation. The requirement of a suboptimal conformation to achieve DNA binding appears to make dicentrine a weaker topoisomerase II inhibitor than the very planar oxoaporphine alkaloid liriodenine. These results suggest that it may be possible to modulate DNA binding and biologic activity of drugs by modifications affecting their ability to adopt planar conformations.
Papaver orientale, Dicentra spectabilis and Chelidonium majus, three Papaveraceae collected from Hokkaido area, were studied for their fungitoxic alkaloids. Ten alkaloids were isolated, identified and tested for their fungitoxic activity. Two of these isolates were found to be new compounds.