Search

Iboga alkaloids are a group of monoterpenoid indole alkaloids with promising and intriguing biological activities. Ibogaine is the representative member of the series and has become widely known as a potent atypical psychedelic with promising effects to treat substance use disorder. Nowadays, an efficient and scalable enantioselective total synthesis of ibogaine and related iboga alkaloids is still lacking, so direct extraction from natural sources or semi-synthetic schemes are the methods of choice to obtain them in a preparative scale. In particular, ibogaine can be obtained either by a low yielding direct isolation from Tabernanthe iboga or using a semi-synthetic procedure from voacangine, an iboga alkaloid occurring in a higher yield in the root bark of Voacanga africana. In this work, we describe an optimized process to obtain voacangine from V. africana root bark as a precursor of the iboga scaffold. Using a direct acetone-based extraction procedure (0.5 kg of root bark), voacangine was isolated in ∼0.8% of root bark dried weight, while the major alkaloids isolated from the bark were identified as iboga-vobasinyl dimers (∼3.7%) such as voacamine and voacamidine. Since these alkaloids contain the voacangine moiety in their structure, the cleavage of the dimers was further optimized, affording an extra amount of voacangine in ∼50% isolated molar yield. In this manner, the total amount of voacangine obtained by application of the whole procedure to the plant material (extraction and dimer cleavage) could almost duplicate the content originally found in the root bark.

Background: Breast cancer could be a serious global health concern causing the best mortality rate in females. Available synthetic medicine to treat breast cancer are marred by extreme toxicity problems and recommend some alternate route to handle the dreadful disease. The present study is an Insilco effort to identify the antitumor potential of Tabernaemontana divaricata plant metabolites.Materials and Methods: The structure of the Human estrogen Receptor (HER), a possible target of breast cancer was selected as target molecules, retrieved from the protein data Bank (PDB) and therefore the structures of alkaloids compounds are collected from PubChem database. Molecular docking and drug similarity studies were performed for these alkaloids compounds to assess and analyze the anti-breast cancer action.Results: The detailed interaction studies of a few alkaloids (Coronaridine, Voacangine, Voacristine, Catharanthine, and Ibogamine) suggest that the compound could serve as probable lead molecules in drug development. All these five compounds also exhibited the highest binding affinity with human ER more significant than 8.7 Kcal/mol which is more affinity as compared to that of standard drugs Tamoxifen.Conclusion: The results of this study is enforced to design novel anti-cancerous medicine within the coming future. The interaction studies of the standard drug with breast cancer markers serve as a tool to synthesize new compounds of desired effectiveness against the deadly disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with yet no effective drug treatment; although several anticholinesterases are being used to offer relief from the symptoms of the disease. Recent studies have indicated that over-activation of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-8 (MMP-8) may cause neuronal death in the brain of AD subjects, suggesting that inhibition of COX-2 and MMP-8 may be of therapeutic value in the management of AD. Therefore, it is important and rational to investigate new agents with anticholinesterase, COX-2 and MMP-8 inhibitory activities. In this study, molecular docking study was performed with earlier identified anticholinesterase alkaloids to search for compounds with high affinity for COX-2 and MMP-8. Molecular docking was done using Blind Docking Server while ligand-protein molecular interaction of compounds with remarkable inhibitory characteristics against COX-2 and MMP-8 were viewed with PyMOL. Alkaloids with high binding affinity and remarkable binding interaction with the target proteins were subjected to drug likeness investigation based on absorption-distribution-metabolism-excretion (ADME) properties using the Swiss online ADME web tool. Nine alkaloids (haloxysterol A, haloxysterol B, haloxysterol C, haloxysterol D, sarcodine, isosarcodine, axillaridine A, sarsalignenone and voacangine hydroxyindolenine) showed high affinities for both COX-2 and MMP-8. Thus, this in silico study identified 9 orally drugable, anticholinesterase alkaloids with COX-2 and MMP-8 multi-target activities that could be studied further as agents against AD.

One new indole alkaloid derivative, 5,6-dioxo-11-hydroxy voacangine (1) together with four known compounds (2-5), were isolated from the fruits of Tabernaemontana inconspicua Stapf (Apocynaceae). T...

Monoterpenoid indole alkaloids (MIAs) of the ibogan type, such as ibogaine, have shown promising antiaddictive effects against several drugs of abuse in humans and animal models of addiction. Unfortunately, international ibogaine demand has led to the overexploitation of natural populations of the African species Tabernanthe iboga (Apocynaceae), the main source of this alkaloid. Therefore, it is necessary to identify alternative ibogan type alkaloid-containing plant species, as well as to develop new sustainable production systems for said group of pharmaceutically important compounds. In this review, we focus on strategies for the in vitro production of the antiaddictive ibogan type MIAs coronaridine, ibogamine, voacangine, and ibogaine (collectively named “CIVI-complex”) from Apocynaceae species, with particular emphasis on the Tabernaemontana genus. Since plant tissue culture (PTC)-related information on the CIVI-complex is scarce, we also consider reports on the in vitro production of other ibogan type MIAs and where necessary, of compounds belonging to the aspidospermatan, corynanthean, and plumeran type. This review aims at giving an overview of potential strategies to produce antiaddictive ibogan type alkaloids from in vitro cultures of Apocynaceae species.

Two new indole alkaloid derivatives, 5,6-dioxo-11-methoxy voacangine (1) and (-)-apparicin-21-one (2), together with four known compounds, voacangine (3), ursolic acid (4), 3-methoxyursolic acid (5) and asiatic acid (6) were isolated from the fruits of Tabernaemontana contorta Stapf (Apocynaceae). Their structures were determined using 1D and 2D NMR and HRESI-MS measurements. The new indole alkaloids were tested on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells to determine their inhibitory effect on nitric oxide (NO) production, but did not have any significant inhibitory activity. Compound (1) slightly increased the proliferation of RAW 264.7 cells in relation with the increased level of NO released by these cells.

Tuberculosis is the main cause of death from a single infectious agent. Globally, according to the World Health Organization, in 2018, there were an estimated 1.2 million tuberculosis deaths. Moreover, there is a continuous appearance of drug-resistant strains. Thus, development of new antituberculosis medicines should receive high priority. Plant-derived natural products are promising candidates for this purpose. We therefore screened alkaloid extracts obtained from the root and stem barks of the Mexican Apocynaceae species Tabernaemontana alba and Tabernaemontana arborea, as well as the pure alkaloids ibogaine, voacangine, and voacamine, tested for activity against Mycobacterium tuberculosis H37Rv and cytotoxicity to mammalian Vero cells using the resazurin microtiter and the MTT assays, respectively. The extracts were analyzed by GC-MS and HPLC-UV. T. arborea root bark alkaloid extract showed the highest activity against M. tuberculosis (MIC100 = 7.8 µg/mL) of the four extracts tested. HPLC suggested that voacangine and voacamine were the major components. The latter was isolated by column chromatography, and its chemical structure was elucidated by 1H and 13C NMR, and MS. Unambiguous assignation was performed by HSQC, HMBC, and NOESY experiments. Voacamine is a dimeric bis-indole-type alkaloid and is 15 times more potent than the monomeric ibogan-type alkaloids ibogaine and voacangine (MIC100 = 15.6, 250.0, and 250.0 µg/mL, respectively). However, all of these compounds showed cytotoxicity to Vero cells, with a poor selectivity index of 1.00, 0.16, and 1.42, respectively. This is the first report of voacamine activity against M. tuberculosis.

Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.

In continuation of our efforts to provide quantitative information on antiaddictive ibogan type alkaloid-producing Tabernaemontana species, we used gas chromatography-mass spectrometry (GC/MS) to compare the alkaloid profiles of the barks and/or leaves of one Mexican and one African species - T. arborea and T. crassa, respectively, with the primary sources of commercially available semisynthetic ibogaine, Voacanga africana root and stem bark. The qualitative and quantitative similarities between T. arborea and V. africana barks consolidate previous reports regarding the potential of the former as a promising alternative source of voacangine and ibogaine. The results also suggest that T. crassa could be used to produce conopharyngine and ibogaline, two compounds with the same basic skeletal structure and possibly similar antiaddictive properties as ibogaine.

Search for natural substances in association with conventional chemotherapeutic drugs with a chemiosensitizing action easily accessible to the tumor mass has encouraged our studies on voacamine (VOA) and its monomeric units, voacangine and vobasine. Our previous results showed that VOA sensitized multidrug resistant (MDR) osteosarcoma cells (U-2 OS/DX) to doxorubicin (DOX) cytotoxicity. VOA, extracted by Peschiera fuchsiaefolia plant, is a bisindole alkaloid consisting of an Iboga skeleton (voacangine) directly linked to a 2-acyl indole unit (vobasine). High-performance thin-layer chromatography densitometry demonstrated the purity of VOA, voacangine and vobasine samples. Flow cytometry analysis showed that VOA, voacangine and vobasine enhanced DOX accumulation of U-2 OS/DX cells, in equally way, whereas VOA reduced more efficiently DOX efflux. Optical microscopy and clonogenic assay confirmed that VOA was more effective than voacangine and vobasine in enhancing DOX cytotoxic effect. These results showed that monomers linked together are necessary to modulate resistant phenotype of osteosarcoma cells. To complete the study, we evaluated the effect of three compounds on microtubules by confocal microscopy, suggesting that only the whole molecule depolymerizes the microtubules blocking so DOX efflux-mediated by vesicles.

Several species from the Apocynaceae family, such as Tabernanthe iboga, Voacanga africana, and many Tabernaemontana species, produce ibogan type alkaloids, some of which present antiaddictive properties. In this study, we used gas chromatography/mass spectrometry (GC/MS) to examine the efficiency of methanol, acetone, ethyl acetate, dichloromethane, chloroform, and hydrochloric acid in extracting the antiaddictive compounds coronaridine, ibogamine, voacangine, and ibogaine (altogether the CIVI-complex) from the root barks of Tabernaemontana alba and Tabernaemontana arborea. These Mexican species have recently shown great potential as alternative natural sources of the aforementioned substances. Methanol proved to be the most suitable solvent. Furthermore, the crude methanolic extracts could be engaged in a one-step demethoxycarbonylation process that converted coronaridine and voacangine directly into its non-carboxylic counterparts ibogamine and ibogaine, respectively, without the intermediacy of their carboxylic acids. The established protocol straightforwardly simplifies the alkaloid mixture from four to two majority compounds. In summary, our findings facilitate and improve both the qualitative and quantitative analysis of CIVI-complex-containing plant material, as well as outlining a viable method for the bulk production of these scientifically and pharmaceutically important substances from Mexican Tabernaemontana species.

Ibogaine and other ibogan type alkaloids present anti-addictive effects against several drugs of abuse and occur in different species of the Apocynaceae family. In this work, we used gas chromatography-mass spectrometry (GC/MS) and principal component analysis (PCA) in order to compare the alkaloid profiles of the root and stem barks of four Mexican Tabernaemontana species with the root bark of the entheogenic African shrub Tabernanthe iboga. PCA demonstrated that separation between species could be attributed to quantitative differences of the major alkaloids, coronaridine, ibogamine, voacangine, and ibogaine. While T. iboga mainly presented high concentrations of ibogaine, Tabernaemontana samples either showed a predominance of voacangine and ibogaine, or coronaridine and ibogamine, respectively. The results illustrate the phytochemical proximity between both genera and confirm previous suggestions that Mexican Tabernaemontana species are viable sources of anti-addictive compounds.

In this work, the plant alkaloid Voacangine, isolated from the bark of Tabernaemontana contorta, was examined as a corrosion inhibitor for steel in 1 M hydrochloric acid. The study was carried out using a comparative approach where several independent methods (spectroscopic solution analysis, electrochemical impedance, potentiodynamic polarisation and mass loss measurements) were performed in order to strengthen the validity of the results. All the findings revealed to be in close agreement with each other. Voacangine was determined to be a mixed corrosion inhibitor and to closely follow Langmuir-type adsorption onto active corrosion sites on the metal surface. The maximal inhibition efficiency was 90% which is lower than other comparable species. This deficiency was ascribed to the presence of a basic nitrogen group causing a degree of steric hindrance for the adsorption.

Currently, no specific licensed antiviral exists for treating the illness caused by dengue virus (DENV). Therefore, the search for compounds of natural origin with antiviral activity is an important area of research. In the present study, three compounds were isolated and identified from seeds of Tabernaemontana cymosa plants. The in vitro antiviral effect of those compounds and voacangine against different DENV strains was assessed using different experimental approaches: compounds added before the infection (Pre), at the same time with the virus (Trans), after the infection (Post) or compounds present in all moments of the experiment (Pre-Trans-Post, Combined treatment). In silico studies (docking and molecular dynamics) were also performed to explain the possible antiviral mechanisms. The identified compounds were three structural analogs of voacangine (voacangine-7-hydroxyindolenine, rupicoline and 3-oxo-voacangine). In the Pre-treatment, only voacangine-7-hydroxyindolenine and rupicoline inhibited the infection caused by the DENV-2/NG strain (16.4% and 29.6% infection, respectively). In the Trans-treatment approach, voacangine, voacangine-7-hydroxyindolenine and rupicoline inhibited the infection in both DENV-2/NG (11.2%, 80.4% and 75.7% infection, respectively) and DENV-2/16681 infection models (73.7%, 74.0% and 75.3% infection, respectively). The latter strain was also inhibited by 3-oxo-voacangine (82.8% infection). Moreover, voacangine (most effective virucidal agent) was also effective against one strain of DENV-1 (DENV-1/WestPac/74) and against the third strain of DENV-2 (DENV-2/S16803) (48.5% and 32.4% infection, respectively). Conversely, no inhibition was observed in the post-treatment approach. The last approach (combined) showed that voacangine, voacangine-7-hydroxyindolenine and rupicoline inhibited over 90% of infections (3.5%, 6.9% and 3.5% infection, respectively) of both strains (DENV-2/NG and DENV-2/16681). The free energy of binding obtained with an in silico approach was favorable for the E protein and compounds, which ranged between −5.1 and −6.3 kcal/mol. Finally, the complex formed between DENV-2 E protein and the best virucidal compound was stable for 50 ns. Our results show that the antiviral effect of indole alkaloids derived from T. cymose depends on the serotype and the virus strain.

Tabernaemontana alba and Tabernaemontana arborea are Apocynaceae species used in Mexican traditional medicine for which little phytochemical information exists. In this study, preliminary gas chromatography/mass spectrometry analyses of different organs obtained from wild plants of both species identified a total of 10 monoterpenoid indole alkaloids (MIAs) and one simple indole alkaloid, nine of which were reported for the first time in these species. Furthermore, callus cultures were established from T. alba leaf explants and regeneration of whole plants was accomplished via somatic embryogenesis. The anti-addictive MIAs ibogaine and voacangine were then quantified by gas chromatography with flame ionization detection in wild plants of both species, as well as greenhouse-grown plants, in vitro-grown plantlets and embryogenic callus of T. alba. Ibogaine and voacangine were present in most samples taken from the whole plants of both species, with stem and root barks showing the highest concentrations. No alkaloids were detected in callus samples. It was concluded that T. alba and T. arborea are potentially viable sources of ibogaine and voacangine, and that these MIAs can be produced through somatic embryogenesis and whole plant regeneration of T. alba. Approaches to increase MIA yields in whole plants and to achieve alkaloid production directly in cell cultures are discussed.

Herbal preparations from Voacanga africana are used in West and Central African folk medicine and are also becoming increasingly popular as a legal high in Europe. Recently, the main alkaloid voacangine was found to be a potent human ether-a-go-go-related gene channel blocker in vitro . Blockage of this channel might imply possible cardiotoxicity. Therefore, the aim of this study was to characterise voacangine in vivo to assess its pharmacokinetics and to estimate if further studies to investigate its cardiotoxic risk are required. Male Wistar rats received different doses of voacangine as a pure compound and as a hydro-ethanolic extract of V. africana root bark with a quantified amount of 9.71 % voacangine. For the obtained data, a simultaneous population pharmacokinetics model was successfully developed, comprising a two-compartment model for i. v. dosing and a one-compartmental model with two first-order absorption rates for oral dosing. The absolute bioavailability of voacangine was determined to be 11–13 %. Model analysis showed significant differences in the first absorption rate constant for voacangine administered as a pure compound and voacangine from the extract of V. africana . Taking into account the obtained low bioavailability of voacangine, its cardiotoxic risk might be neglectable in healthy consumers, but may have a serious impact in light of drug/drug interactions and impaired health conditions.

Flowers of Tabernaemontana divaricata (L.) R. Br., (Apocynaceae) are used in traditional medicine for analgesic property. The present study was performed to isolate the active principles and investigate the mechanisms involved in the anti-nociception caused by T. divaricata flower methanolic extract (TDFME). The extract in the doses of 125, 250 and 500 mg/kg, p.o was subjected to various assays in acetic acid induced abdominal writhing and formalin induced paw licking test models. Naloxone, L-Arginine, Glibenclamide and Glutamate were used as inducers while Morphine, L-NAME, Methylene blue and Aspirin served as standard drugs. The phytochemical analysis led to the isolation of three indole alkaloids namely Voacangine, Catharanthine and O-acetyl Vallesamine. The anti-nociception produced by TDFME was attenuated significantly (p< 0.001) by the intra-peritoneal pretreatment of naloxone, L-Arginine and glibenclamide. The nociception produced by glutamate was inhibited by TDFME. TDFME also enhanced the antinociceptive activity of L-NAME when given in combination. However TDFME co-administration did not produce significant results with methylene blue indicating lack of cGMP involvement. These results indicate that TDFME produces anti-nociception action mediated by opioid, nitric oxide, K+-ATP and glutamate mechanisms and the effect is largely related to the indole alkaloids.

Four alkaloids, voacangine (1), isovoacangine (2), coronaridine (3), and coronaridine hydroxyindolenine (4), were isolated from the MeOH extract of Tabernaemontana divaricata aerial parts by activity-guided fractionation for Wnt signal inhibitory activity. Compounds 1-4 exhibited TCF/β-catenin inhibitory activities with IC50 values of 11.5, 6.0, 5.8, and 7.3 μM, respectively. Of these, coronaridine (3) decreased β-catenin levels in SW480 colon cancer cells, while this decrease in β-catenin was not suppressed by a co-treatment with 3 and MG132, a proteasome inhibitor. These results suggested that the decrease observed in β-catenin levels by coronaridine (3) did not depend on a proteasomal degradation process. On the other hand, the treatment of SW480 cells with coronaridine (3) caused a decrease in β-catenin mRNA levels. Thus, coronaridine (3) may inhibit the Wnt signaling pathway by decreasing the mRNA expression of β-catenin.

This study was carried out to isolate active ingredients from Voacanga africana Stapf (Apocynaceae) used as herbal medicine in Cameroon, and also to assess the efficacy of the compounds on Onchocerca ochengi and Loa loa worms. The compounds were isolated using solvent partitioning, column chromatography and fractional crystallization. The O. ochengi worms were isolated from cow skin while Loa loa was isolated from humans. Filaricidal activity was determined based on motility for adult male worms and microfilariae (Mfs), while adult female worm viability was assessed biochemically by the dimethylthiazol (MTT)/formazan assay. Cytotoxicity was assessed using monkey kidney epithelial cells. Auranofin was used as the positive control drug. Two compounds, voacangine (compound 1) and voacamine (compound 2) were isolated from the stem bark of Voacanga africana. Both compounds were found to inhibit the motility of both the microfilariae (Mfs) and adult male worms of O. ochengi in a concentration-dependent manner, but were only moderately active on the adult female worms upon biochemical assessment at 30 µM drug concentration. The IC50s for voacangine were 5.49 µM for Mfs and 9.07 µM for adult male worms; while for voacamine the values were 2.49 µM for Mfs and 3.45 µM for adult males. At 10 µM, voacamine showed 100% inhibition of Loa loa Mfs motility after 24 h. This is the first report of the anti-Onchocerca activity of voacangine (compound 1) and voacamine (compound 2) as well as activity of voacamine (compound 2) on L. loa. The results of this study support the traditional use of V. africana in the treatment of human onchocerciasis. Key words: Voacanga africana, voacangine, voacamine, anti-Onchocerca activity.

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine’s principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure–activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

Virtual Screening and Molecular Docking analysis for Tabernaemontana divaricata derived 66 Law Molecular Weight Compounds (LMW) was conducted and to identified and predicted novel molecules as a inhibitor of Streptococcus pneumonia. The investigation has revealed several compounds with optimum binding towards Penicillin-binding proteins, Sialidases, Aspartate betasemialdehide dehydrogenase cell membrane protein of Streptococcus pneumonia. Docking results were computed in term of binding energy, ligand efficiency and number of hydrogen bonding. Apparicine (-5.14), 5-Hydroxyvoaphylline (-4.78), Voacangine (-4.7), 19-Hydroxycoronaridine (-4.44) and Coronaridine (-4.72) are identified as most suitable to bind with N-acetylglucosamine-1- phosphate uridyltransferase receptor. Ervaticine (-6.33), Ibogamine (-6.15), Methylvoaphylline (-5.74) and Coronaridine hydroxyindolenine (-5.32) has showed novel binding against the penicillin-binding proteins. Ervaticine (-6.42), 5-oxo-11-hydroxy voaphylline (-6.18), Conolobine B (-6.02) has found optimum binding against the active site of NanB sialidase of Streptococcus pneumonia. The compounds 3S-Cyanocoronaridine (-6.71), 19-Epivoacristine (-5.48) and Ervaticine(-5.45) interacting with aspartate beta-semialdehide and found suitable with least docking score.

Voacangine (1) is an alkaloid found in the root bark of Voacanga africana. Our previous work has suggested that 1 is a novel transient receptor potential vanilloid type 1 (TRPV1) antagonist. In this study, the agonist and antagonist activities of 1 were examined against thermosensitive TRP channels. Channel activity was evaluated mainly using TRP channel-expressing HEK cells and calcium imaging. Herein, it was shown that 1 acts as an antagonist for TRPV1 and TRPM8 but as an agonist for TRPA1 (EC50, 8 μM). The compound competitively blocked capsaicin binding to TRPV1 (IC50, 50 μM). Voacangine (1) competitively inhibited the binding of menthol to TRPM8 (IC50, 9 μM), but it showed noncompetitive inhibition against icilin (IC50, 7 μM). Moreover, the compound selectively abrogated chemical agonist-induced TRPM8 activation and did not affect cold-induced activation. Among these effects, the TRPM8 inhibition profile is unique and noteworthy, because to date no studies have reported a menthol competitive inhibitor of TRPM8 derived from a natural source. Furthermore, this is the first report of a stimulus-selective TRPM8 antagonist. Accordingly, 1 may contribute to the development of a novel class of stimulus-selective TRPM8 blockers.

Ethnopharmacological relevance Bacterial infections remain a significant threat to human health. Due to the emergence of widespread antibiotic resistance, development of novel antibiotics is required in order to ensure that effective treatment remains available. There are several reports on the ethnomedical use of Tabernaemontana elegans pertaining to antibacterial activity. Aim of the study The aim of this study was to isolate and identify the fraction responsible for the antimicrobial activity in Tabernaemontana elegans (Stapf.) root extracts. Materials and methods The active fraction was characterized by thin layer chromatography (TLC) and gas chromatography–mass spectrometry (GC–MS). Antibacterial activity was determined using the broth micro-dilution assay and antimycobacterial activity using the BACTEC radiometric assay. Cytotoxicity of the crude extract and fractions was assessed against primary cell cultures; lymphocytes and fibroblasts; as well as a hepatocarcinoma (HepG2) and macrophage (THP-1) cell line using the Neutral Red uptake and MTT assays. Results The crude root extracts were found to contain a high concentration of alkaloids (1.2%, w/w). GC–MS analysis identified the indole alkaloids, voacangine and dregamine, as major components. Antibacterial activity was limited to the Gram-positive bacteria and Mycobacterium species, with MIC values in the range of 64–256 μg/ml. When combined with antibiotics, additive antibacterial effects were observed. Marked cytotoxicity to all cell lines tested was evident in the MTT and Neutral Red uptake assays, with IC50 values Conclusions This study confirms the antibacterial activity of Tabernaemontana elegans and supports its potential for being investigated further for the development of a novel antibacterial compound.

Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a critical role in normal and pathological phenotypes, including solid tumor growth and metastasis. Accordingly, the development of new anti-angiogenic agents is considered an efficient strategy for the treatment of cancer and other human diseases linked with angiogenesis. We have identified voacangine, isolated from Voacanga africana, as a novel anti-angiogenic agent. Voacangine inhibits the proliferation of HUVECs at an IC(50) of 18 μM with no cytotoxic effects. Voacangine significantly suppressed in vitro angiogenesis, such as VEGF-induced tube formation and chemoinvasion. Moreover, the compound inhibits in vivo angiogenesis in the chorioallantoic membrane at non-toxic doses. In addition, voacangine decreased the expression levels of hypoxia inducible factor-1α and its target gene, VEGF, in a dose-dependent manner. Taken together, these results suggest that the naturally occurring compound, voacangine, is a novel anti-angiogenic compound.

Voacanga africana (Apocynaceae) is used as an anti-diarrheal medicine in West Africa. In the present study, we investigated the effect of an extract of V. africana and its constituents on smooth muscle contraction induced by capsaicin in mouse rectum, where transient receptor potential vanilloid type 1 (TRPV1)-immunoreactive fibers are abundant. Methanol and alkaloid extracts of the root bark of V. africana were found to inhibit capsaicin-induced contraction in a dose-dependent manner (30-300 μg/ml). Major constituents isolated from the alkaloid extract were then studied for their effects on the capsaicin-induced contraction. The main active constituents were found to be Iboga-type alkaloids, including voacangine (1), 3-oxovoacangine (2), voacristine (3), and (7α)-voacangine hydroxyindolenine (4). The voacangine concentration dependently (3-100 μM) inhibited the capsaicin-induced contraction. The capsaicin-induced contraction was almost completely inhibited by the TRPV1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). On the other hand, the Iboga-type alkaloids did not inhibit the contractions induced by 3 μM acetylcholine and 300 μM nicotine. These results suggest that Iboga-type alkaloids isolated from V. africana inhibit capsaicin-induced contraction in the mouse rectum, possibly via the inhibition of a TRPV1-mediated pathway. This inhibition may be involved in the anti-diarrheal effect of V. africana.

The leaves of Voacanga foetida (Bl.) Rolfe, have been used ethnomedically for the treatment of wounds, itches, and swellings particularly in Lombok island. A phytochemical study has been done to investigate chemical compounds responsible against the cause of the diseases. By separating alkaloidal fraction from the leaves was found voacristine 1 as the major alkaloidal compound, and voacangine 2 and coronaridine 3 as the minor components. The structure elucidation of the compounds was carried out on the basis of spectroscopy data. A structure revision of voacristine 1 was also reported. Keywords: alkaloids, Voacanga foetida, Lombok

Voacanga africana (Apocynaceae) is a small tropical African tree. The root bark and seeds of this tree contain a number of alkaloids, including ibogaine (a hallucinogenic/aphrodisiac compound in bark), tabersonine (a major constituteent of seeds) and other voacanga alkaloids, traditionally used in Africa for religious purposes. Recently, some kinds of products containing this plant (root bark and seeds) have been distributed in the drug market in expectation of its hallucinogenic/aphrodisiac effects. There has been no report that has discussed quantitative analyses of these alkaloids in the products and their botanical origins. In this study, to investigate the trend of such a non-controlled psychotropic plant of abuse, a simultaneous analytical method was developed using LC/MS for the voacanga alkaloids including ibogaine and tabersonine in the commercial products of V. africana. Moreover, the botanical origins of these products were investigated by DNA analyses. As a result of the LC/MS analyses, the products were classified into two chemical types; an ibogaine-type and a tabersonine-type. The samples of the ibogaine-type contain ibogaine (0.05-0.6%) and other voacanga alkaloids; voacamine, voacamidine and voacangine, while those of the tabersonine-type mainly contain tabersonine (0.6-1.6%). The sequence analyses of chloroplast DNA, trnL-F region suggested that most of the products were derived from V. africana or closely related plants. They were classified into four genotypes based on nucleotide sequence of the trnL-F IGS region. The proposed methods of chemical and DNA analyses would be useful for investigating the trend in the distribution of the products of V. africana.

A necessidade da introdução de novos agentes quimioterápicos é uma realidade no controle de doenças infecciosas. O Brasil é o país mais rico em biodiversidade, e o Laboratório de Extração da Universidade Paulista tem coletado plantas na Amazônia e Mata Atlântica com a finalidade de identificar extratos vegetais antibacterianos e antitumorais. Estudos prévios demonstraram que a fração etanólica obtida do extrato bruto orgânico do caule de Tabernaemontana angulata Mart. ex Müll. Arg. apresentou atividade antimicrobiana significante contra Staphylococcus aureus ATCC6538, no ensaio de diluição em caldo. Verificou-se por cromatografia em camada delgada que os compostos majoritários presentes na fração ativa eram alcalóides. No presente trabalho, foi obtida a fração de alcalóides totais a partir do extrato bruto, da qual os compostos majoritários foram isolados por sucessivas cromatografias e, posteriormente, identificados por CG-EM e ¹H-RMN como os alcalóides indólicos coronaridina e voacangina. As frações obtidas do isolamento foram testadas no ensaio biológico, porém não demonstraram atividade antimicrobiana. Introducing new chemotherapeutic agents is a great demand in the control of infectious diseases. Brazil is one of the richest countries in biodiversity and the Laboratório de Extração at UNIP has been collecting plants from the Amazon and Atlantic Rain Forests with the aim of screening for new antibacterial and antitumor plant extracts. Previous studies demonstrated that the ethanol fraction obtained from the crude extract of Tabernaemontana angulata stems showed an antibacterial activity against Staphylococcus aureus (ATCC 6538) in the microdilution broth assay. Two alkaloids were the major compounds in the active fraction, verified by thin layer chromatography analysis. In the present study, the total alkaloids were obtained from the crude extract and were fractionated by preparative thin layer chromatography for the isolation of the main components. The isolated compounds were identified by GC/MS and ¹H-NMR as coronaridine and voacangine. The alkaloid fractions obtained from the isolation procedure were tested for antibacterial activity, but no activity was detected.

Six known alkaloids iboga type and the triterpen α- and β-amyrin acetate were isolated from the roots and stems of Peschiera affinis. Their structures were characterized on the basis of spectral data mainly NMR and mass spectra. 1D and 2D NMR spectra were also used to unequivocal ¹H and 13C chemical shift assignments of alkaloids. The ethanolic extract of roots, alkaloidic and no-alkaloidic fractions and iso-voacristine hydroxyindolenine and voacangine were evaluated for their antioxidative properties using an autographic assay based on β-carotene bleaching on TLC plates, and also spectrophotometric detection by reduction of the stable DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical.

The aim of this study was: i) to carry out a structural analysis of ibogaine and noribogaine, ii) to identify products formed under light exposure (daylight or 254 nm, 20°C) of the two drugs in methanolic solutions, and iii) to examine the alkaloid contents of a specimen of root bark of the Tabernanthe iboga shrub using liquid chromatography‐electrospray mass spectrometry. After daylight exposure, two oxidation products were detected: ibochine and iboluteine from ibogaine, and desmethoxyibochine and desmethoxyiboluteine from noribogaine. After exposure to 254 nm of the ibogaine solution, another compound that could possibly be the analogous lactam of iboluteine was detected. From the liquid chromatography electrospray‐mass spectrometry analysis of the root barks of a specimen of the Tabernanthe iboga shrub, seven alkaloids were detected: ibochine (m/z 325), ibogaline (m/z 341), iboluteine (m/z 327), ibogaine (m/z 311), ibogamine (m/z 281) and voacangine (m/z 369). The last compound characterized ...

A new monoterpenoid indole alkaloid compound (1) and six known monoterpenoid indole alkaloids compounds (2–7) were isolated from the barks of Voacanga africana Staph. The structures were established by spectral analysis as ibogamine-16-carboxylic acid,17,20-didehydro-5,6-dioxo-10-methoxy-methyl ester (1), voacamine (2), vobasine (3), voacangine (4), voacristine (5), 19-epi-voacristine (6) and 19-epi-heyneanine (7). Compound 1 was confirmed by X-ray crystallographic analysis. All of the isolated compounds were evaluated for cytotoxicity against five cell lines (HEPG-2, A375, MDA-MB-231, SH-SY5Y, CT26). Among them, compounds 2 and 6 displayed significant inhibitory activities, compounds 3, 4 and 5 showed moderate inhibitory activities, while compounds 1 and 7 showed no inhibitory activities against the five cell lines.

Indole alkaloids from Tabernaemontana catharinensis, collected from different places, were extracted using a mixture of supercritical CO2 plus ethanol. The effects of the process variables: temperature, pressure, solvent flow rate, and percentage of cosolvent on the total yield, chemical composition of the extract, and extraction kinetics were determined. The extracts were solvent-partitioned and their composition analyzed by TLC, GC-MS and 1H and 13C NMR. Voacangine and coronaridine were identified as the major compounds in the extracts; the individual alkaloids were quantified by GC-FID using external standard. At 250 bar and 45 °C the largest yield (1.29%) and the faster extraction rate were obtained; increasing the percentage of cosolvent improved the extraction rate as well as the yield. Employing an intermittent process consisting in six pressurization–depressurization steps appreciably reduced the total extraction time.

The iboga alkaloid voacangine (1) has been reported previously to be the first stimulus-selective TRPM8 antagonist. In the present report, a structure-activity relationship (SAR) study is described on the effects of some naturally occurring indole alkaloid analogues on TRPM8 inhibition. Dihydrocatharanthine (10) and catharanthine (11) were found to be inhibitors of TRPM8 activity, and their IC50 values were equivalent to that of BCTC, a potent and representative TRPM8 antagonist. Furthermore, it was shown that the iboga moiety is the most crucial unit for TRPM8 blockade and that its stereostructure, as found in 1 but not in 10 and 11, is essential for chemical agonist-selective TRPM8 inhibition. These findings should provide useful information for synthesizing additional stimulus-selective and TRPM8-selective blockers.

Through bioassay-guided fractionation and chromatography technique, eight indole alkaloids were furnished from the stems of Ervatamia hainanensis. All isolates were evaluated for acetylcholinesterase (AChE) inhibition activities, in which compounds 1 and 3 exhibited the same level of activities as galantamine, a marketed cholinesterase inhibitor for the treatment of Alzheimer's disease. Discussion about the relationships between structure and activity of these alkaloids was also presented.

Tissue lines, selected from explants of Tabernanthe iboga H. Bn. and cultured in shake flasks, produced and released from three to five indole alkaloids into the culture medium. the iboga alkaloids in order of their relative abundance were ibogaine, dihydroxyibogamine, ibogamine, voacangine, and ibogaline. All five compounds have the same basic ring structure as ibogaine, a putative anti-addictive drug. Three of these could consistently be detected in culture medium that was removed and replaced at two-week intervals over periods of at least five months. the nutrient-hormone combination used consisted of Gamborg's B5 medium with 2% w/v sucrose, 2mg/l 2,4-dichlorophenoxy-acetic acid (2,4-D) and 0.1 mg/16-benzyladenine (BA). These results suggest that plant tissue culture procedures can be developed as an economically feasible and environmentally responsible source of ibogaine and other potential anti-addictive drugs.