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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.

To determine whether (+)-catharanthine induces sedative- or anxiolytic/anxiogenic-like activity in male mice, proper animal paradigms were used. The results showed that (+)-catharanthine induces sedative-like activity in the 63–72 mg/Kg dose range in a flumazenil-insensitive manner, but neither this effect nor anxiolytic/anxiogenic-like activity was observed at lower doses. To determine the underlying molecular mechanism of the sedative-like activity, electrophysiological and radioligand binding experiments were performed with (+)-catharanthine and (±)-18-methoxycoronaridine [(±)-18-MC] on GABAA (GABAARs) and glycine receptors (GlyRs). Coronaridine congeners both activated and potentiated a variety of human (h) GABAARs, except hρ1. (+)-Catharanthine-induced potentiation followed this receptor selectivity (EC50's in μM): hα1β2 (4.6 ± 0.8) > hα2β2γ2 (12.6 ± 3.8) ~ hα1β2γ2 (14.4 ± 4.6) indicating that both α1 and α2 are equally important, whereas γ2 is not necessary. (+)-Catharanthine was >2-fold more potent and efficient than (±)-18-MC at hα1β2γ2. (+)-Catharanthine also potentiated, whereas (±)-18-MC inhibited, hα1 GlyRs with very low potency. Additional [3H]-flunitrazepam competition binding experiments using rat cerebellum membranes clearly demonstrated that these ligands do not bind to the benzodiazepine site. This is supported by the observed activity at hα1β2 (lacking the BDZ site) and similar effects between α1- and α2-containing GABAARs. Our study shows, for the first time, that (+)-catharanthine induced sedative-like effects in mice, and coronaridine congeners potentiated human α1β2γ2, α1β2, and hα2β2γ2, but not ρ1, GABAARs, both in a benzodiazepine-insensitive fashion, whereas only (+)-catharanthine slightly potentiated GlyRs.

Two new monoterpene indole alkaloids, isoakuammiline (1) and 18-hydroxypseudovincadifformine (2), and five known alkaloids, coronaridine (3), heyneanine (4), 3,19-oxidocoronaridine (5), tabersonine, and strictosidine, were identified from the fruit of Tabernaemontana litoralis. The structures of the alkaloids were determined using NMR and MS data analyses. While 18-hydroxypseudovincadifformine (2) showed a new hydroxylation pattern, isoakuammiline (1) revealed a novel skeleton for monoterpene indole alkaloids. In spite of the isolation of stemmadenine from the fruit tissues in other Tabernaemontana species, this vital biosynthetic precursor of iboga, aspidosperma, and pseudoaspidosperma skeletons was not found in T. litoralis.

The primary aim of this study was to determine the anti-neuropathic activity of (±)-18-methoxycoronaridine [(±)-18-MC] and (+)-catharanthine in mice by using the oxaliplatin-induced neuropathic pain paradigm and cold plate test. The results showed that both coronaridine congeners induce anti-neuropathic pain activity at a dose of 72 mg/kg (per os), whereas a lower dose (36 mg/kg) of (+)-catharanthine decreased the progress of oxaliplatin-induced neuropathic pain. To determine the underlying molecular mechanism, electrophysiological recordings were performed on α9α10, α3β4, and α4β2 nAChRs as well as voltage-gated calcium (CaV2.2) channels modulated by G protein-coupled γ-aminobutyric acid type B receptors (GABABRs). The results showed that (±)-18-MC and (+)-catharanthine competitively inhibit α9α10 nAChRs with potencies higher than that at α3β4 and α4β2 nAChRs and directly block CaV2.2 channels without activating GABABRs. Considering the potency of the coronaridine congeners at Cav2.2 channels and α9α10 nAChRs, and the calculated brain concentration of (+)-catharanthine, it is plausible that the observed anti-neuropathic pain effects are mediated by peripheral and central mechanisms involving the inhibition of α9α10 nAChRs and/or CaV2.2 channels.

The inhibitory activity of coronaridine congeners on human (h) α4β2 and α7 nicotinic acetylcholine receptors (AChRs) is determined by Ca2+ influx assays, whereas their effects on neurons in the ventral inferior (VI) aspect of the mouse medial habenula (MHb) are determined by patch-clamp recordings. The Ca2+ influx results clearly establish that coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to hα4β2 and hα7 subtypes, and with the following potency sequence, for hα4β2: (±)-18-methoxycoronaridine [(±)-18-MC] > (+)-catharanthine > (±)-18-methylaminocoronaridine [(±)-18-MAC] ∼ (±)-18-hydroxycoronaridine [(±)-18-HC]; and for hα7: (+)-catharanthine > (±)-18-MC > (±)-18-HC > (±)-18-MAC. Interestingly, the inhibitory potency of (+)-catharanthine (27 ± 4 μM) and (±)-18-MC (28 ± 6 μM) on MHb (VI) neurons was lower than that observed on hα3β4 AChRs, suggesting that these compounds inhibit a variety of endogenous α3β4* AChRs. In addition, the interaction of bupropion with (−)-ibogaine sites on hα3β4 AChRs is tested by [3H]ibogaine competition binding experiments. The results indicate that bupropion binds to ibogaine sites at desensitized hα3β4 AChRs with 2-fold higher affinity than at resting receptors, suggesting that these compounds share the same binding sites. In conclusion, coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to other AChRs, by interacting with the bupropion (luminal) site. Coronaridine congeners also inhibit α3β4*AChRs expressed in MHb (VI) neurons, supporting the notion that these receptors are important endogenous targets for their anti-addictive activities.

In previous studies, we demonstrated the leishmanicide effect of coronaridine, a natural indole alkaloid isolated from stem bark ofPeschiera australis(Delorenzi et al., Antimicrob. Agents Chemother.45:1349-1354, 2001). In this study we show the leishmanicidal effect of the synthetic coronaridine and its racemic 18-methoxylated analog, 18-methoxycoronaridine. Both alkaloids revealed a potent leishmanicide effect againstLeishmania amazonensis, a causative agent of cutaneous and diffuse cutaneous leishmaniasis in the New World. Despite their potent leishmanicide effect, both alkaloids were neither toxic to murine macrophages nor did they modulate their oxidative or cytokine production responses.

In this study, we show the leishmanicidal effects of a chloroform fraction (CLF) and a purified indole alkaloid obtained from crude stem extract ofPeschiera australisagainstLeishmania amazonensis, a causative agent of cutaneous leishmaniasis in the New World. In a bioassay-guided chemical fractionation, the leishmanicidal activity in CLF completely and irreversibly inhibited promastigote growth. This fraction was also active against amastigotes in infected murine macrophages. Chemical analysis of CLF identified an iboga-type indole alkaloid coronaridine as one of its major compounds. Coronaridine showed potent antileishmanial activity, inhibiting promastigote and amastigote growth. Promastigotes and amastigotes treated with CLF or coronaridine showed pronounced alterations in their mitochondria as assessed by transmission electron microscopy.

A new bisindole alkaloid, 19,20-dihydroervahanine A was isolated from the stems of Ervatamia coronaria grown in Brazil, together with five known alkaloids: coronaridine, heyneanine, voacristine, voacamine, descarbomethoxyvoacamine and five phenolic acids: vanillic, gentisic, syringic, 4-hydroxybenzoic and salicylic acid. The aqueous and alcoholic extracts, when administered p.o. or i.p. to rats 1 h before subplantar injection of carrageenin had a significant anti-inflammatory effect. The alcoholic extract also had an analgesic effect and increased the pentobarbital induced sleeping time.

Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addiction to opioid and stimulant drugs and has been reported to decrease morphine and cocaine self-administration in rats. The present study sought to determine if other iboga alkaloids, as well as the chemically related harmala alkaloid harmaline, would also reduce the intravenous self-administration of morphine and cocaine in rats. Because both ibogaine and harmaline induce tremors, an effect that may be causally related to neurotoxicity in the cerebellar vermis, the temorigenic activities of the other iboga alkaloids were assessed. Lastly, in view of the involvement of the dopaminergic mesolimbic system in the actions of drugs of abuse, the effects of some of the iboga alkaloids on extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum were determined. All of the tested alkaloids (i.e., ibogaine, tabernanthine, R- and S-coronaridine, R- and S-ibogamine, desethylcoronaridine, and harmaline) dose-dependently (2.5–80 mg/kg) decreased morphine and cocaine intake in the hour after treatment; decreases in morphine and cocaine intake intake were also apparent the day after administration of some but not all of these alkaloids (i.e., ibogaine, tabernanthine, desethylcoronaridine, and the R-isomers of coronaridine and ibogamine). In some rats, there were persistent decreases in morphine or cocaine intake for several days after a single injection or after two or three weekly injections of one or another of these alkaloids; R-ibogamine produced such effects more consistently than any of the other alkaloids. At the doses used to assess effects on drug self-administration, ibogaine, tabernanthine, desethylcoronaridine and harmaline all induced tremors for at least 2–3 h; both enantiomers of both coronaridine and ibogamine induced very weak or no tremors. Using in vivo microdialysis, the effects of the R- and S-enantiomers of coronaridine and ibogamine on extracellular dopamine levels in the nucleus accumbens and striatum were compared. The R-enantiomers decreased dopamine levels in both brain regions whereas the S-enantiomers produced no significant changes in dopamine levels in either region. The results of this study indicate that the ‘anti-addictive’ and tremorigenic effects of the iboga alkaloids can be dissociated and that long-term effects of these alkaloids on drug self-administration appear to be related to initial decreases in dopaminergic activity in specific brain areas.

Seven indole alkaloids (coronaridine, tabersonine, olivacine, coronaridine-hydroxyindolenine, catharinensine, decarbomethoxyvoacamine AND tabernamine) were isolated from Peschiera australis in Brazil. Four phenolic acids (vanillic acid, syringic acid, gentisic acid AND salicylic acid) were also found. Crude extracts of P. australis seeds AND leaves showed in vivo antineoplastic activity against two experimental tumor models: Ehrlich's carcinoma AND Sarcoma 180. Aqueous AND alcohol leaf extracts administered to rats 1 h before subplantar carrageenan injection had a significant dose-related anti-inflammatory effect. The same extracts also showed analgesic activity against acetic acid-induced abdominal writhing.

A new alkaloid designated as ervatine, in addition to seven known alkaloids, viz. tabersonine, coronaridine, heyneanine, voacristine, voacristine hydroxyindolenine, hydroxyibogamine, and coronaridine hydroxyindolenine, were isolated from the fruit of Tabernaemontana heyneana Wall. Characterisation and structure elucidation of these compounds was made on the basis of their spectral analyses. The ethanolic extract and isolated alkaloids heyneanine and voacristine prevented pregnancy when administered during the preimplantation period in Sprague-Dawley rats. These were, however, found to possess significant uterotrophic activity.

A new monoterpenoid indole alkaloid, 15,20-dehydro-3α-(2-oxopropyl) coronaridine (1), along with sixteen analogues (2–17) were isolated from the leaves of Catharanthus roseus cultivated in Yunnan. The new alkaloid was elucidated on the basis of extensive spectroscopic analysis, and the known alkaloids were identified by comparison with the reported spectroscopic data. Among them, alkaloid 16 was isolated from Catharanthus for the first time.

The Iboga alkaloid congener 18-methoxycoronaridine (18-MC) exhibits in vitro leishmanicidal and in vivo anti-addiction properties. In this paper, we describe that 18-MC inhibits HIV-1 infection in human peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages. We found that 18-MC inhibits the replication of primary isolates of HIV-1 in a dose-dependent manner, regardless of the preferential chemokine receptor usage of the isolates, at non-cell-toxic concentrations. The antiretroviral activity of 18-MC resulted in EC (50) values of 22.5 +/- 4.7 microM and 23 +/- 4.5 microM for R5 and X4 isolates, respectively, in PBMCs, and a therapeutic index (TI) of 14.5. Similar findings were observed for inhibition of HIV-1 replication in macrophages: EC (50) equal to 12.8 +/- 5 microM and 9.5 +/- 3 microM for an R5 virus after 14 and 21 days of infection, respectively, with TI equal to 25.6 and 34.5. 18-MC moderately inhibits the HIV-1 enzyme reverse transcriptase (IC (50) = 69.4 microM), which at least partially explains its antiretroviral activity.

Bioassay-directed fractionation of the alkaloid portion of a CH(2)Cl(2)-MeOH extract of Tabernaemontana calcarea resulted in the isolation of the three new cytotoxic indole alkaloids, 1-3, and the 12 known alkaloids voacangine (4), isovoacangine (5), coronaridine (6), 11-hydroxycoronaridine (7), voacristine (8), 19-epi-voacristine (9), isovoacristine (10), ibogamine (11), 10-methoxyibogamine (12), 11-methoxyibogamine (13), heyneanine (14), and 19-epi-heyneanine (15). The structures of the new compounds 1-3 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic interpretation. All the compounds exhibited cytotoxic activity against the A2780 ovarian cancer cell line.

Coronaridine [1], conoduramine [2], and voacamine [3], three indole alkaloids isolated from Peschiera laeta, have been found to enhance the cytotoxic response mediated by vinblastine [4] with multidrug-resistant KB cells. Inhibition of vinblastine binding with membrane vesicles isolated from this cell line was also assessed, and the bisindole alkaloids conoduramine [2] and voacamine [3] were found to be more potent inhibitory agents than the monomeric alkaloid, coronaridine [1]. Thus, these compounds appear to function by binding with P-glycoprotein.

Assays using radioligands were used to assess the actions of ibogaine and harmaline on various receptor types. Ibogaine congeners showed affinity for opiate receptors whereas harmaline and harmine did not. The Ki for coronaridine was 2.0 microM at mu-opiate receptors. The Kis for coronaridine and tabernanthine at the delta-opiate receptors were 8.1 and 3.1 microM, respectively. Ibogaine, ibogamine, coronaridine and tabernanthine had Ki values of 2.08, 2.6, 4.3 and 0.15 microM, respectively, for kappa-opiate receptors. Long-lasting, dose-dependent behavioral effects of ibogaine have been reported. The possibility that these effects were due to irreversible binding properties of ibogaine at kappa-receptors was considered; however, radioligand wash experiments showed a rapid recovery of radioligand binding after one wash. A voltage-dependent sodium channel radioligand demonstrated Ki values in the microM range for all drugs tested. Using radioligand binding assays and/or 36Cl- uptake studies, no interaction of ibogaine or harmaline with the GABA receptor-ionophore was found. The kappa-activity of ibogaine (or an active metabolite) may be responsible for its putative anti-addictive properties whereas the tremorigenic properties of ibogaine and harmaline may be due to their effects on sodium channels.

The hormone profile of coronaridine hydrochloride an antifertility agent of plant origin was investigated. Oral administration of 30 mg/kg prevented pregnancy in rats when given on Days 1 2 3 or 4 postcoitum. The effect on Days 5 6 7 or 8 was only partial. This substance showed estrogenic activity but was devoid of antiestrogenic androgenic antiandrogenic progestational antiprogestational and uterine stimulant activities. However there was a partial inhibition of oxytocin-induced uterine response. This compound appears to exert its antifertility action due to its frank estrogenicity.

Cell suspension cultures of TABERNAEMONTANA DIVARICATA were found to produce relatively large amounts of indole alkaloids. For their isolation an ion-pair DCCC method was used in combination with preparative TLC. The alkaloids were identified as tabernaemontanine, perivine, vobasine, voaphylline, voaphylline-hydroxyindolenine, vallesamine, apparicine, 16-hydroxy-16,22-dihydroapparicine, pericyclivine, tubotaiwine, 19- S-heyneanine, and coronaridine. Voaphylline, the main alkaloid, was produced during growth and early stationary phase and reached a maximum of 23 mg/l at day 19 of the growth cycle. After this maximum voaphylline was rapidly metabolized. Apparicine, vobasine, and coronaridine reached their maximum levels at a later stage of the growth cycle. Tubotaiwine accumulation showed a similar profile as that of voaphylline. In light-grown cells the total production was about 2 times higher than in dark-grown cells, with respective main products voaphylline and apparicine.

A simple test is described in which the inhibition of uptake of [G-3H]thymidine into guinea-pig ear keratinocytes in vitro, has been used as an assessment for cytotoxicity of a series of alkaloids. The alkaloids tested include emetine, colchicine, coronaridine, ajmaline, aricine, vincristine, leurosine, quinamine, 3-epiquinamine, quinine, quinidinone, cichonidine, berberine and atropine.

The taxonomy, phytochemistry, ethnobotany, and pharmacology of the genus Tabernaemontana L. (Apocynaceae) is reviewed. The genus is currently being revised taxonomically; most of the segregate genera are being reunited with it and the number of species that will ultimately be recognized will probably be about 100. All the names encountered in the chemical and ethnobotanical literature have been evaluated as far as possible, and a list is presented of the recognized species and their synonyms. The biogenesis and classification of the indole alkaloids found in Tabernaemontana species is set out and some problems in the determination of their stereochemistry are discussed. To facilitate access to the information, three lists have been compiled: the alkaloids in alphabetical order; the alkaloids in order of increasing molecular weight; and the alkaloids grouped according to their biogenetic classification, together with the species and plant part(s) in which they are known to occur. Biogenetic and chemotaxonomic aspects are briefly considered. A table of the non-alkaloidal constituents is also included. The ethnobotany of individual Tabernaemontana species is outlined and an overall assessment made. Likewise, information on the pharmacology of crude extracts and individual alkaloids from Tabernaemontana species has been assembled and appraised.

Conopharyngine, the major alkaloid present in the leaves of Tabernaemontana (Conopharyngia) pachysiphon var. cumminsi (Stapf) H. Huber was isolated and identified by Thomas & Starmer (1963). The same alkaloid has also been found in the stem bark of a Nigerian variety of the same species by Patel & Poisson (1966) and in the stem bark of Conopharyngia durissima by Renner, Prins & Stoll (1959). Conopharyngine is an indole alkaloid of the voacanga type, being 18-carbomethoxy-12,13dimethoxyibogamine (Fig. 1) and is thus closely related to voacangine and coronaridine.

The structure of albifloranine 1, a new alkaloid of ibogane type from the stem bark of Tabernaemontana albiflora (M IQ.) Pull. (Apocynaceae) has been determined. A detailed (1)H NMR study of albifloranine 1, coronaridine 2 and heyneanine 3 is presented.

Eleven monomeric indole alkaloids have been isolated from the roots of Ervatamia hainanensis. Nine of them are known: coronaridine 1, coronaridine hydroxyindolenine 2, heyneanine 3, vobasine 4, perivine 5, ibogamine 6, geissoschizol 7, 10-hydroxygeissoschizol 8 and 3-oxocoronaridine 9; and two are new: 10-hydroxyheyneanine 10 and 3-(beta-hydroxyethyl)-coronaridine 11.

From the seeds of TABERNAEMONTANA DICHOTOMA, the alkaloids coronaridine, ibogamine, stemmadenine, tabersonine, voacangine, voaphylline and voaphylline hydroxyindolenine were isolated and identified. The crude seed extract showed spasmolytic activity.

The isolation of the alkaloids from two different samples of stem bark of Tabernaemontana psorocarpa is described. Both samples contained 16-epi-isositsirikine as the major alkaloid but differed from each other in the number and quantity of the other alkaloids. The following minor alkaloids were identified: 12-methoxy-14,15-dehydro-vincamine, vallesiachotamine, isovallesiachotamine, tetrahydroalstonine, coronaridine and voacangine.

The crude acetic acid extract of TABERNAEMONTANA DICHOTOMA fruits showed convulsive and spasmolytic activity. From the chloroform soluble fraction of this extract, eleven indole alkaloids were isolated and identified as (-)-apparicine, coronaridine, 3-ketopropylcoronaridine, dichomine, 19 R-epiheyneanine, isomethuenine, 12 methoxy-voaphylline, voaphylline, vobasine, vallesamine and O-acetyl-vallesamine.

The leaves and stems of T. JASMINOIDES have been found to contain indole alkaloids. Five indole alkaloids, coronaridine, voacangine, apparicine, conoflorine, and 19-epi-voacangarine have been isolated. The 13 C-NMR spectra of apparicine and 19-epi-voacangarine are also reported.

The whole plant of Ervatamia coronaria var. plena obtained from Thailand has afforded a new indole alkaloid 19S-heyneanine hydroxyindolenine whose structure was deduced through interpretation of spectral data. Nine known alkaloids, coronaridine, coronaridine hydroxyindolenine, voacangine, voacangine hydroxyindolenine, heyneanine, voacristine, 3-oxo-coronaridine, 3-oxo-voacangine,and voacristine hydroxyindolenine, and six common triterpenoids were also isolated. Coronaridine was the principal cytotoxic alkaloid obtained.

Stemmadenine, the major alkaloid from the seeds of Tabernaemotana dichotoma , showed hypotensive activity and weak muscle relaxant activity. Perivine, vobasine, coronaridine and dichomine, some of the alkaloids found in the leaves, fruits and bark of T. dichotoma , also showed hypotensive and muscle relaxant activity.

Cancer has become a major public health problem worldwide and the number of deaths due to this disease is increasing almost exponentially. In the constant search for new treatments, natural products of plant origin have provided a variety of new compounds to be explored as antitumor agents. Tabernaemontana catharinensis is a medicinal plant that produces alkaloids with expressive antitumor activity, such as heyneanine, coronaridine and voacangine. The aim of present study was firstly to screen the cytotoxic activity of the indole alkaloids heyneanine, coronaridine and voacangine against HeLa (human cervix tumor), 3T3 (normal mouse embryo fibroblasts), Hep-2 (human laryngeal epithelial carcinoma) and B-16 (murine skin) cell lines by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); and secondly to analyze the apoptotic activity, cell membrane damage and genotoxicity of the compound that showed the best cytotoxic activity against the tumor cell lines tested. Coronaridine was the one that exhibited greater cytotoxic activity in the laryngeal carcinoma cell line Hep-2 (IC50 = 54.47 µg/mL) than the other alkaloids tested (voacangine IC50 = 159.33 µg/mL, and heyneanine IC50 = 689.45 µg/mL). Coronaridine induced apoptosis in cell lines 3T3 and Hep-2, even at high concentrations. The evaluation of genotoxicity by comet assay showed further that coronaridine caused minimal DNA damage in the Hep-2 tumor cell line, and the LDH test showed that it did not affect the plasma membrane. These results suggest that further investigation of coronaridine as an antitumor agent has merit.

Obtention d'oxo-5- et -6 coronaridines, d'hydroxy-5 oxo-6 coronaridine et de derives oxygenes de l'ibogamine, de la seco-2,7 coronaridine et de bicoronaridinyle-5,10'