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Two new monoterpenoid indole alkaloids, named taberibogines E and F ( 1 and 2 ), together with three known ones ( 3 - 5 ) were isolated from the stems of Tabernaemontana bovina Lour (Apocynaceae). Their structures including absolute configurations were elucidated from a combination of NMR and HRESIMS data and NMR calculations as well as DP4+ probability analyses. Compounds 1 and 2 exhibited inhibitory effects on LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages.

The opioid epidemic and limited access to treatment for opioid withdrawal (OW) and opioid use disorder (OUD) has led individuals to seek alternative treatments. This narrative review aims to educate clinicians on the mechanisms of action, toxicity, and applications of psychoactive plant-based substances patients may be using to self-treat OUD and OW. We specifically discuss ayahuasca, ibogaine, and kratom as they have the most evidence for applications in OUD and OW from the last decade (2012-2022). Evidence suggests these substances may have efficacy in treating OW and OUD through several therapeutic mechanisms including their unique pharmacodynamic effects, rituals performed around ingestion, and increased neuroplasticity. The current evidence for their therapeutic application in OUD and OW is primarily based on small observational studies or animal studies. High-quality, longitudinal studies are needed to clarify safety and efficacy of these substances in treatment of OW and OUD.

Ethnopharmacological Relevance: The Tabernaemontana genus belongs to the Apocynaceae family of which 30 species are found in Brazil. Some Tabernaemontana species are used by Brazilian indigenous people and other communities, or are listed in the Yanomami Pharmacopeia. Ethnopharmacological data include use(s) for muscle problems, depressed sternum, back pain, abscess, indigestion, eye irritation, earache, itching, vaginal discharge, as an aid for older people who are slow and forgetful, mosquito and snake bites, infection by the human botfly larvae, calmative, and fever. Obviously, many of these uses are attributed to the alkaloids found in Tabernaemontana species., Aim of the Review: The aim is to gather information on Tabernaemontana species occurring in Brazil, as sources of monoterpene indole alkaloids (MIAs). In addition, we aim to collect reported experimental demonstrations of their biological activity, which may provide the foundation for further studies, including phytochemistry, the development of medicinal agents, and validation of phytopreparations., Material and Methods: The Brazilian Flora 2020 database was used as source for Tabernamontana species occurring in Brazil. The literature review on these species was collected from Web of Science, Scopus, PubMed, and Scifinder. The keywords included names and synonyms of Tabernaemontana species found in Brazil, which were validated by the Word Flora Online Plant List., Results: A literature survey covering the time frame from 1960 until June 2023 resulted in 121 MIAs, including 48 not yet reported in the last review published in 2016. Some alkaloid extracts, fractions, and isolated alkaloids present evidenced biological activity, such as anticancer, anti-inflammatory, antinociceptive, antimicrobial, antiparasitic, antiviral, and against snake venoms, among others. Notably, ethnopharmacological based information has been the basis of some reports on Tabernaemontana species., Conclusions: Our literature survey shows that Tabernaemontana species present bioactive MIAs, such as voacamine and affinisine, demonstrating significant cytotoxicity activity against several tumoral cell lines. Those compounds can be considered promising candidates in the search for new anticancer drugs. However, the Amazonian plant biome is increasingly damaged, which may lead to the extinction of biological diversity. This threat may also affect Tabernaemontana species, which have scarcely been investigated regarding the potential of their phytochemicals for the development of new drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Natural products contribute substantially to anticancer therapy; the plant kingdom provides an important source of molecules. Conofolidine is a novel Aspidosperma-Aspidosperma bisindole alkaloid isolated from the Malayan plant Tabernaemontana corymbosa . Herein, we report conofolidine's broad-spectrum anticancer activity together with that of three other bisindoles-conophylline, leucophyllidine, and bipleiophylline-against human-derived breast, colorectal, pancreatic, and lung carcinoma cell lines. Remarkably, conofolidine was able to induce apoptosis (e.g., in MDA-MB-468 breast) or senescence (e.g., in HT-29 colorectal) in cancer cells. Annexin V-FITC/PI, caspase activation, and PARP cleavage confirmed the former while positive β-gal staining corroborated the latter. Cell cycle perturbations were evident, comprising S-phase depletion, accompanied by downregulated CDK2, and cyclins (A2, D1) with p21 upregulation. Confocal imaging of HCT-116 cells revealed an induction of aberrant mitotic phenotypes-membrane blebbing, DNA-fragmentation with occasional multi-nucleation. DNA integrity assessment in HCT-116, MDA-MB-468, MIAPaCa-2, and HT-29 cells showed increased fluorescent γ-H2AX during the G1 cell cycle phase; γ-H2AX foci were validated in HCT-116 and MDA-MB-468 cells by confocal microscopy. Conofolidine increased oxidative stress, preceding apoptosis- and senescence-induction in most carcinoma cell lines as seen by enhanced ROS levels accompanied by increased NQO1 expression. Collectively, we present conofolidine as a putative potent anticancer agent capable of inducing heterogeneous modes of cancerous cell death in vitro, encouraging further preclinical evaluations of this natural product.

Six undescribed bisindole alkaloids, namely taberdisines A-F (1-6), were isolated from the leaves of Tabernaemontana divaricata 'Dwaft'. Among them, alkaloids 1 and 2 were the first examples of strychnos-iboga type alkaloid with both C-C linkage patterns. Alkaloid 3, a new type of aspidosperma-iboga with a furan-ring, as well as other three undescribed ones was disclosed. Their structures were elucidated by comprehensive spectroscopic analyses. Alkaloids 1 and 5 showed insecticide activity on Sf9 cell and eggs of Spodoptera frugiperda in vivo, which might explain the potential of the plants for insect resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Seventeen undescribed Aspidosperma-type alkaloids (ASPs), along with nine known ones were isolated from the leaves of Tabernaemontana bovina. Taberbovermines A and B were assigned to tabersonine-type with a contracted A- and E-ring, respectively. Taberbovermine C was attributed to tabersonine without D ring. These structures of the ASPs were established on the basis of comprehensive spectroscopic data, electronic circular dichroism calculations and X-ray diffraction. The summaries of structure-activity relationship of tabersonine class were discussed based on hepatoma cells screening., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tabernaemontana arborea (Apocynaceae) is a Mexican tree species known to contain ibogan type alkaloids. This study aimed at determining central nervous system-related activities of an alkaloid extract obtained from the root bark of T. arborea. A gas chromatography-mass spectrometry (GC-MS) analysis was performed to describe the alkaloid profile of the extract. A wide dosing range (0.1 to 56.2 mg/kg) of this extract was evaluated in different murine models. Electrical brain activity was examined by electroencephalography (EEG). The extract's effects on motor coordination, ambulatory activity, and memory were analyzed based on the rotarod, open field (OFT), and object recognition tests (ORT), respectively. Antidepressant and antinociceptive activities were determined using the forced swimming test (FST) and the formalin assay, respectively. In order to elucidate the underlying mechanisms of action, the 5-HT 1A receptor antagonist WAY100635 (1 mg/kg) or the opioid receptor antagonist naloxone (1 mg/kg) was included in the latter experiments. GC-MS analysis (μg/mg extract) confirmed the presence of the monoterpenoid indole alkaloids (MIAs) voacangine (207.00), ibogaine (106.33), vobasine (72.81), coronaridine (30.72), and ibogamine (24.2) as principal constituents of the extract, which exhibited dose- and receptor-dependent antidepressant (0.1 to 1 mg/kg; 5-HT 1A ) and antinociceptive (30 and 56.2 mg/kg; opioid) effects, without altering motor coordination, ambulatory activity, and memory. EEG indicated CNS depressant activity at high doses (30 and 56.2 mg/kg). The root bark of T. arborea contains a mixture of alkaloids that may hold therapeutic value in pain relief and the treatment of psychiatric diseases without causing neurotoxic activity at effective doses., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The iboga alkaloids scaffold shows great potential as a pharmacophore in drug candidates for the treatment of neuropsychiatric disorders. Thus, the study of the reactivity of this type of motif is particularly useful for the generation of new analogs suitable for medicinal chemistry goals. In this article, we analyzed the oxidation pattern of ibogaine and voacangine using dioxygen, peroxo compounds, and iodine as oxidizing agents. Special focus was placed on the study of the regio- and stereochemistry of the oxidation processes according to the oxidative agent and starting material. We found that the C 16 -carboxymethyl ester present in voacangine stabilizes the whole molecule toward oxidation in comparison to ibogaine, especially in the indole ring, where 7-hydroxy- or 7-peroxy-indolenines can be obtained as oxidation products. Nevertheless, the ester moiety enhances the reactivity of the isoquinuclidinic nitrogen to afford C 3 -oxidized products through a regioselective iminium formation. This differential reactivity between ibogaine and voacangine was rationalized using computational DFT calculations. In addition, using qualitative and quantitative NMR experiments combined with theoretical calculations, the absolute stereochemistry at C 7 in the 7-hydroxyindolenine of voacangine was revised to be S , which corrects previous reports proposing an R configuration.

The structures of the recently published monoterpene indole alkaloids penduflorines A and B (1a and 1b), isolated from Tabernaemontana penduliflora (Apocynaceae), have been revised. Rather than an inseparable mixture of two compounds, they appear to be the known alkaloid vobasine (2). Although we could not comprehensively revise the structures of penduflorines C-E due to lacking spectral data, since their structural elucidations were based on that of 1a and 1b, their structures should also be treated with caution., Competing Interests: Declaration of Competing Interest There are no conflicts to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Eight undescribed iboga alkaloids, polyneurines A-H, were isolated from the bark of Tabernaemontana polyneura. The structures of these alkaloids were established by interpretation of the MS and NMR data, while the configurations were determined using GIAO NMR calculations and DP4+ probability analysis, TDDFT-ECD method, or X-ray diffraction analysis. Polyneurine A possesses a γ-lactone unit embedded within the iboga skeleton, while polyneurines D and E incorporate a formylmethyl moiety at C-3 of the iboga skeleton. Biosynthetic pathways towards the formation of polyneurines A, C, D, and E were proposed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Eleven monoterpenoid indole alkaloids, including three new ones, tabercrassines A-C ( 1 - 3 ), were isolated from the seeds of Tabernaemontana crassa . Tabercrassine A ( 1 ) is an ibogan-ibogan-type bisindole alkaloid which is formed by the polymerization of two classic ibogan-type monomers through a C3 unit aliphatic chain. Their structures were established by extensive analysis of HRESIMS, NMR, and ECD spectra. Cellular assays showed that alkaloids 1 - 3 all reduce A β 42 production and inhibit phospho-tau (Thr217), a new biomarker of Alzheimer's disease [AD] associated with BACE1-, NCSTN-, GSK3β-, and CDK5-mediated pathways, suggesting these alkaloids' potential against AD.

Extraction methods like maceration, ultrasonication, vortex mixer, soxhlet extraction and microwave assisted extraction (MAE), were evaluated for the extraction of Camptothecin (CPT) from the leaves and stem of Tabernaemontana alternifolia , Tabernaemontana divaricata and Tabernaemontana citrifolia . The extracts were analyzed by high performance thin layer chromatography (HPTLC). The results show that the leaves of Tabernaemontana alternifolia exhibited highest yield of CPT as compared to the other species. MAE was the most efficient extraction method with CPT extraction yield of 0.154 ± 0.004% w/w from Tabernaemontana alternifolia leaves followed by Soxhlet extraction, sonication, maceration, and vortex extraction methods.

Two new alkaloids, taberdines L ( 1 ) and M ( 2 ), together with six known alkaloids, were isolated from the twigs and leaves of Tabernaemontana divaricata . Taberdine L ( 1 ) represents the first optically active natural member of the allo iboga class of alkaloids with the ethyl side chain in a bridgehead position. Their structures including absolute configuration were elucidated by a combination of MS, NMR, and ECD calculation. The in vitro cytotoxic activities of 1 and 2 against five human cancer cell lines were also evaluated.

Two iboga-vobasine bisindoles, 16'-decarbomethoxyvoacamine (1: ) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2: ) from Tabernaemontana corymbosa exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1: and 2: selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1: and 2: suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2: was chosen for the subsequent studies. Bisindole 2: inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an in vitro tubulin polymerization assay and molecular docking analysis showed that bisindole 2: is a microtubule-stabilizing agent which is predicted to bind at the β -tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21 Cip1 /Chk1, and p21 Cip1 /Rb/E2F, as shown by microarray profiling., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Thirteen indole alkaloids comprising six vobasine/sarpagine, one vincamine, two voaphylline, two tacaman, one iboga, and one corynantheine alkaloid, were isolated from the leaf extract of Tabernaemontana corymbosa (sample from Taiping, Perak, Malaysia). The structures of these alkaloids were determined based on analysis of the spectroscopic data (NMR and MS), and in the case of vincarudine, the absolute configuration was established by ECD and X-ray diffraction analysis. Vobasidine E represents the first vobasine-type alkaloid characterized by a contracted ring C and loss of the ethylidene/ethyl side chain. A possible biogenetic pathway from a perivine precursor, which was also present in the leaf extract, is presented. Differences in the new alkaloid content between the present and previous sample of the same plant (occurring in a different location) are discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Phytochemical investigation on the aerial parts of Tabernaemontana bufalina Lour. (Apocynaceae) led to the identification of four undescribed monoterpenoid indole alkaloids named taberbufamines A-D, an undescribed natural product, and fourteen known indole alkaloids. The structures of the undescribed alkaloids were established by spectroscopic and computational methods, and their absolute configurations were further determined by quantum chemical TDDFT calculations and the experimental ECD spectra. Taberbufamines A and B possessed an uncommon skeleton incorporating an indolizidino [8,7-b]indole motif with a 2-hydroxymethyl-butyl group attached at the pyrrolidine ring. Biosynthetically, Taberbufamines A and B might be derived from iboga-type alkaloid through rearrangement. Vobatensine C showed significant bioactivity against A-549, Bel-7402, and HCT-116 cells with IC 50 values of 2.61, 1.19, and 1.74 μM, respectively. Ervahanine A showed antimicrobial activity against Bacillus subtilis, Mycobacterium smegmatis, and Helicobacter pylori with MIC values of 4, 8, and 16 μg/mL, respectively. 19(S)-hydroxyibogamine was shown as butyrylcholinesterase inhibitor (IC 50 of 20.06 μM) and α-glycosidase inhibitor (IC 50 of 17.18 μM), while tabernamine, ervahanine B, and ervadivaricatine B only showed α-glycosidase inhibitory activities with IC 50 values in the range of 0.95-4.61 μM., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Tabernaemontana corymbosa is a traditional folk medicine. In our research, six monoterpene indole N-oxide alkaloids and their parent alkaloids were obtained from the stem bark of T. corymbosa, including seven new alkaloids (1-7) and five known alkaloids (8-12). Their structures and absolute configurations were elucidated by extensive spectroscopy, quantum chemical calculations, and DP4+ probability analyses. The antimicrobial activity of the obtained compounds was evaluated, among which alkaloids 4, 8, 12 showed significant antimicrobial activity against Staphylococcus aureus with an MIC value of 6.25 μg/mL, while alkaloids 11, 12 showed moderate antimicrobial activity against Bacillus subtilis with an MIC value of 25 μg/mL., (Copyright © 2022. Published by Elsevier B.V.)

Tabernaecorymine A, an 18-normonoterpenoid indole alkaloid with conjugated (E)-3-aminoacrylaldehyde fragment was obtained from the stem bark of Tabernaemontana corymbosa. Its structure was elucidated by extensive spectroscopic data analyses, and further verified by ACD/structure elucidator, electronic circular dichroism (ECD) analyses and density functional theory (DFT) chemical shift predictions. The compound exhibited significant antibacterial bioactivity against Streptococcus dysgalactiae with an MIC value of 3.12 μg/mL, which is better than the plant drug berberine., (Copyright © 2022. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Ervatamia coronaria, a popular garden plant in India and some other parts of the world is known traditionally for its anti-inflammatory and anti-cancer properties. The molecular bases of these functions remain poorly understood., Aim of the Study: Efficacies of the existing therapies for colorectal cancer (CRC) are limited by their life-threatening side effects and unaffordability. Therefore, identifying a safer, efficient, and affordable therapeutic is urgent. We studied the anti-CRC activity of an alkaloid-rich fraction of E. coronaria leaf extracts (AFE) and associated underlying mechanism., Materials and Methods: Activity guided solvant fractionation was adopted to identify the activity in AFE. Different cell lines, and tumor grown in syngeneic mice were used to understand the anti-CRC effect. Methodologies such as LCMS, MTT, RT-qPCR, immunoblot, immunohistochemistry were employed to understand the molecular basis of its activity., Results: We showed that AFE, which carries about six major compounds, is highly toxic to colorectal cancer (CRC) cells. AFE induced cell cycle arrest at G1 phase and p21 and p27 genes, while those of CDK2, CDK-4, cyclin-D, and cyclin-E genes were downregulated in HCT116 cells. It predominantly induced apoptosis in HCT116p53+/+ cells while the HCT116p53-/- cells under the same treatment condition died by autophagy. Notably, AFE induced upregulation of AMPK phosphorylation, and inhibition of both of the mTOR complexes as indicated by inhibition of phosphorylation of S6K1, 4EBP1, and AKT. Furthermore, AFE inhibited mTOR-driven conversion of cells from reversible cell cycle arrest to senescence (geroconversion) as well as ERK activity. AFE activity was independent of ROS produced, and did not primarily target the cellular DNA or cytoskeleton. AFE also efficiently regressed CT26-derived solid tumor in Balb/c mice acting alone or in synergy with 5FU through inducing autophagy as a major mechanism of action as indicated by upregulation of Beclin 1 and phospho-AMPK, and inhibition of phospho-S6K1 levels in the tumor tissue lysates., Conclusion: AFE induced CRC death through activation of both apoptotic and autophagy pathways without affecting the normal cells. This study provided a logical basis for consideration of AFE in future therapy regimen to overcome the limitations associated with existing anti-CRC chemotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The first stage of the drug discovery process involves the identification of small compounds with biological activity. Iboga alkaloids are monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring. Both the natural products and the iboga-inspired synthetic analogs have shown a wide variety of biological activities. Herein, we describe the chemoenzymatic preparation of a small library of novel N -indolylethyl-substituted isoquinuclidines as iboga-inspired compounds, using toluene as a starting material and an imine Diels-Alder reaction as the key step in the synthesis. The new iboga series was investigated for its potential to promote the release of glial cell line-derived neurotrophic factor (GDNF) by C6 glioma cells, and to inhibit the growth of infective trypanosomes. GDNF is a neurotrophic factor widely recognized by its crucial role in development, survival, maintenance, and protection of dopaminergic neuronal circuitries affected in several neurological and psychiatric pathologies. Four compounds of the series showed promising activity as GDNF releasers, and a leading structure (compound 11 ) was identified for further studies. The same four compounds impaired the growth of bloodstream Trypanosoma brucei brucei (EC 50 1-8 μM) and two of them (compounds 6 and 14 ) showed a good selectivity index.

Four new iboga-type alkaloids, ervaoffines H-K (1-4), along with five known compounds were obtained from the aerial parts of Ervatamia officinalis. The absolute configurations of 1-4 were confirmed by X-ray diffraction and electronic circular dichroism (ECD) analyses. The isolates were tested for their anti-inflammatory activity. Compounds 1, 5, 6, and 9 showed potential inhibitory effect of NO production in LPS-stimulated BV2 and RAW264.7 cells., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Continued interest in bioactive monoterpenoid indole alkaloids and the purpose to explore the artificial cultivation influence on the chemical composition in the same plant species, 8 undescribed Aspidosperma-type alkaloids including two unprecedented trimers, taberdivarines A-B (1-2), and six new dimers, taberdivarines CH (3-8), together with 9 known bisindoles were isolated from the leaves of Tabernaemontana divaricata 'Dwaft'. Notably, taberdivarines A and B were the first cases of Aspidosperma-Aspidosperma-Aspidosperma-type alkaloids with furan ring linkage patterns of the natural products. Their structures were elucidated by comprehensive spectroscopic analyse. Compounds 1-8 were screened for the cytotoxicity against three human cancer cell lines, SMMC-7721, HT-29 and A549. Among them, Compound 6 exhibited significant activity against three cell lines with IC 50 values of 0.30, 0.75 and 3.41 μM, respectively (IC 50  = 3.02, 0.14 and 2.23 μM for the positive control, vinorelbine). Compound 1, 3, 4, 6, 7 and 8 also expressed varying degrees of activity. The structure-activity relationships (SARs) of these alkaloids were discussed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Five undescribed carboxy-indole alkaloids with corynanthe skeleton, penduflorines A-E (1-3) as well as a voacangine-N-oxide alkaloid, tabernaemontine (4), were isolated along with eight other known compounds (5-12) from the trunk bark of Tabernaemontana penduliflora K. Schum (Apocynaceae). Their structures were determined by means of spectroscopic and spectrometric methods such as UV, IR, NMR and HR-ESI-MS. Antiplasmodial activities of new isolates were evaluated against two strains of Plasmodium falciparum 3D7 and Dd2 by the Sybr green I-based fluorescence assay setup. Those compounds showed good in vitro activities. Among them, penduflorines A and B (1a and 1b) as well as tabernaemontine (4) showed significant inhibitory activities against the two strains with IC 50 values ranged between 1.85 and 7.88 μg/mL. This is the first report of quaternary-N-indole alkaloids (1a, 1b, 2, 3a, 3b and 4) occurring in the form of zwitterion from Tabernaemontana genus., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alkaloids are a group of secondary metabolites that have been widely studied for the discovery of new drugs due to their properties on the central nervous system and their anti-inflammatory, antioxidant and anti-cancer activities. Molecular docking was performed for 10 indole alkaloids identified in the ethanol extract of Tabernaemontana cymosa Jacq. with 951 human targets involved in different diseases. The results were analyzed through the KEGG and STRING databases, finding the most relevant physiological associations for alkaloids. The molecule 5-oxocoronaridine proved to be the most active molecule against human proteins (binding energy affinity average = -9.2 kcal/mol) and the analysis of the interactions between the affected proteins pointed to the PI3K/ Akt/mTOR signaling pathway as the main target. The above indicates that indole alkaloids from T. cymosa constitute a promising source for the search and development of new treatments against different types of cancer.

Two new bisindole alkaloids, bisnaecarpamines A (1) and B (2), possessing a vobasine-sarpagine type skeleton were isolated from the bark of Tabernaemontana macrocarpa Jack. Their structures were elucidated by extensive spectroscopic methods and chemical correlation. The absolute configurations of compounds 1 and 2 were established using TDDFT-ECD calculation of the selected isomers. Bisnaecarpamine A exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC 50 value of 28.8 µM.

A new cerebroside, Contortamide ( 1 ) together with nine known compounds spegatrine ( 2 ), affinisine ( 3 ), Nb-methylaffinisine ( 4 ), ursolic acid ( 5 ), α-amyrin ( 6 ), bauerenol acetate ( 7 ), lupeol ( 8 ), betulinic acid ( 9 ) and β-sitosterolglycoside ( 10 ) were isolated from the trunk bark of Tabernaemontana contorta Stapf. The new compound 1 showed significant activity against Caco-2 colon cancer cells with the MTT method. Compounds 1-4 and 6-9 were isolated for the first time from this species.

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). Their structures were determined using 1D and 2D NMR, HRESI-MS, and a comparison with the literature. The new compound was found to be cytotoxic on human breast cancer MDA-MB 231 cells with IC 50 values of 3.35 µM and 2.19 µM after 24 and 48 hours, respectively.

Covering: 2000 up to 2020 Few classes of natural products have inspired as many chemists and biologists as have the iboga alkaloids. This family of monoterpenoid indole alkaloids includes the anti-addictive compound ibogaine as well as catharanthine, a precursor to the chemotherapeutic vinblastine. Despite being known for over 120 years, these small molecules continue to challenge our assumptions about biosynthetic pathways, catalyze our creativity for constructing complex architectures, and embolden new approaches for treating mental illness. This review will cover recent advances in both the biosynthesis and chemical synthesis of iboga alkaloids as well as their use as next-generation neurotherapeutics. Whenever appropriate, we provide historical context for the discoveries of the past decade and indicate areas that have yet to be resolved. While significant progress regarding their chemistry and pharmacology has been made since the 1960s, it is clear that the iboga alkaloids will continue to stoke scientific innovation for years to come.

Nineteen indole alkaloids including eleven new ones, taberdines A-K (1-11), were isolated from Tabernaemontana divaricata. Their structures were assigned by MS, NMR, single crystal X-ray diffractions, and ECD analyses. Alkaloid 1 is an aspidosperma-type monoterpenoid indole alkaloid and possesses a rearranged pyrrolidine moiety due to C-3 degradation, and 4 has a rare 1,3-oxazolidine moiety within iboga-type alkaloids. Alkaloids 2, 4, 6, and 11-19 combined with 5 μg/mL fluconazole exhibited significant activity to reverse fluconazole resistance in Candida albicans strains while no one used alone showed any activities against the resistant strain., (Copyright © 2020 Elsevier Inc. All rights reserved.)

K-Ras is one of the most important oncogenes in human oncogenesis. K-Ras transfection of normal rat fibroblasts induces phenotypic change from flat to round morphology. Then, we screened compounds inducing flat morphology in K-Ras transformed fibroblasts from microbial culture filtrates and plant extracts. As a result, the alkaloid conophylline was isolated from the leaves of Ervatamia microphylla collected in Thailand. Conophylline induced flat morphology and inhibited cellular invasion in K-Ras-transformed normal rat kidney (K-Ras-NRK) cells. It also inhibited the growth of the K-Ras-NRK tumor in mice. Cancer-associated fibroblasts are now considered to activate cancer growth. Conophylline was found to suppress secretions of various inflammatory cytokines by pancreatic cancer-associated fibroblasts. Moreover, when combined with gemcitabine, it inhibited the growth of pancreatic cancer growth in mice. Conophylline is orally active. Thus, the plant-derived alkaloid conophylline inhibited cancer growth directly and indirectly, and it shows promise as a new anticancer agent.

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals 1 . Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting 2 , which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling 3,4 . However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Twenty-one aspidosperma-aspidosperma alkaloids, including the new tabernaesines A-J ( 1 - 9 ), were obtained from Tabernaemontana pachysiphon . The structures and absolute configurations were elucidated using HRMS and NMR experiments. Compounds 1 - 9 possessed a rare spiro heterocycle moiety between the monomeric units, while compounds 4 and 5 were characterized by an indole ring fused with an ( N , N -diethyl)methyl amino group. Compounds 1 , 5 - 7 , 15 , and 16 exhibited moderate cytotoxic potency against various human cancer cell lines at IC 50 2.5-9.8 μM.

Twenty-six alkaloids, including the new taberines A-I ( 1 - 9 ), were obtained from Tabernaemontana corymbosa . The structures and absolute configurations were elucidated via MS, NMR, and ECD spectroscopic data analyses. Alkaloids 1 - 4 are new vobasinyl-ibogan alkaloids, and 1 is characterized by an unusual 1,3-oxazinane moiety. Alkaloids 4 and 16 exhibited moderate cytotoxic potency against various human cancer cell lines, while 4 , 10 , 11 , 13 , 14 , and 16 showed attenuation of lysosomal acidification activity (EC 50 : 12.9-29.8 μM), thereby inhibiting autophagic flux.

The aim of this study was to evaluate the most effective extraction condition (temperature, solvent type and time) for recovery of high-value phytochemicals present in the Tabernaemontana catharinensis leaves (TC) and to assess their effect on biochemical parameters in streptozotocin-induced diabetic rats. The extraction of phenolic compounds from TC using a factorial design (FD) 2³, high performance liquid chromatography (HPLC), response surface methodology (RSM) and principal component analysis (PCA) were studied. It was found that the optimal conditions for extraction of phenolics were higher temperature (65 °C) and time (60 min) using ethanol as extractor solvent. In this condition of extraction (A8), total phenolic compounds (TPC) and antioxidant activity (AA) were determined. Additionally, this extract was used to evaluate their effect on antioxidant enzyme activities (superoxide dismutase (SOD) and catalase (CAT)) as well as lipid peroxidation (LP) and protein thiols level (PSH) in the liver and kidneys of normal and diabetic rats. As result, T. catharinensis extract presented TPC content of 23.34 mg EAG/g (equivalent gallic acid) and AA of 34.26 μmol Trolox/g. Phenolic acids (ferulic acid and coumaric acid) and flavonoids (quercetin, rutin and pinocembrin) could be recovered and identified by HPLC. This study indicated an important role of the T. catharinensis extract on free radical inactivation and on the antioxidant defense system in diabetic rats. In fact, the use of T. catharinensis extract restored the normal activity of SOD ( p < 0.05) and suppressed malondialdehyde levels in liver and kidney tissues. Thus, the T. catharinensis extract, rich in phenolic compounds, can be responsible for the recover the enzymatic changes in the liver and kidney tissues provoked by diabetes in rats. In addition, the lipid peroxidation rate decreased in the diabetic rats treated with T. catharinensis .

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., (© 2020 Wiley-VHCA AG, Zurich, Switzerland.)

Coronaridine ( 1 ) was isolated from the CH 2 Cl 2 root extract of Tabernaemontana ternifolia. The structure of 1 was established from 1D- and 2D-NMR and HR-ESIMS experiments, and by comparison with reported spectroscopic data. To date, this is the first report of compound 1 from T. ternifolia, introduced as new Tabernaemontana species from Philippines in 2005 on the basis of morphological characters. Coronaridine, an iboga-type indole alkaloid, has been isolated from over 50 Tabernaemontana species and can thus be inferred as a chemotaxonomic marker of the genus. T. ternifolia has a distinct arrangement of leaves not known in the genus, but is variable in other genera. Its isolation from endemic T. ternifolia establishes its position in the genus and supports the claim that coronaridine is a chemical marker of the genus Tabernaemontana. Interestingly, coronaridine exhibited relatively weak activity against Mycobacterium tuberculosis H 37 Rv (MIC 82.64 μg/mL) (Rifampicin MIC 0.05 μg/mL).

Cycloaddition reactions generate chemical complexity in a single step. Here we report the crystal structures of three homologous plant-derived cyclases involved in the biosynthesis of iboga and aspidosperma alkaloids. These enzymes act on the same substrate, named angryline, to generate three distinct scaffolds. Mutational analysis reveals how these highly similar enzymes control regio- and stereo-selectivity.

Aspidosperma alkaloids, a subclass of monoterpenoid indole alkaloids rich in the Apocynaceae plants, possess remarkable antitumor activities, but the underlying mechanisms have rarely been reported. In the current project, 11-methoxytabersonine (11-MT), an aspidosperma-type alkaloid isolated from Tabernaemontana bovina, significantly inhibited the viability of two human lung cancer cell lines A549 and H157, and the molecular mechanisms were thus investigated. The results showed that 11-MT killed lung cancer cells via induction of necroptosis in an apoptosis-independent manner. In addition, 11-MT strongly induced autophagy in the two cell lines, which played a protective role against 11-MT-induced necroptosis. Finally, the autophagy caused by 11-MT was found to be via activation of the AMP activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and the c-Jun N-terminal kinase (JNK) signaling pathways in both cells. Taken together, 11-MT exhibited an antitumor mechanism different from that of previously reported analogues and could have the potential to serve as a lead compound for the development of new chemotherapy for lung cancer.

Aims: In the present study, the flavonoid fraction of Tabernaemontana divaricata flavonoid fraction(TdFf) leaves was investigated for its in vitro and in vivo antioxidative and antitumor activity., Subjects and Methods: The flavonoid fraction of ethyl acetate extract was assessed for their in vitro antioxidant activity by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), superoxide radicals, ferric reducing antioxidant power (FRAP), hydrogen peroxide, hydroxyl radicals and nitric oxide and in vivo antioxidative activity by enzymic and nonenzymic antioxidants in the liver of intraperitoneally implanted Ehrlich's lymphoma (EAC) and Dalton's lymphoma ascites (DLAs) model. The in vitro cytotoxicity was assessed using trypan blue exclusion assay and in vivo antitumor activity was assessed by screening the ILS, serum liver marker enzymes and histopathology of the liver., Statistical Analysis Used: The data were expressed as the mean ± standard deviation of the means, and statistical analysis was carried out employing one-way and two-way analysis of variance using Web Agri Stat Package 2.0., Results: The dose-dependent percentage scavenging of ABTS, DPPH, FRAP, OH, superoxide radical, and nonradical NO and H 2 O 2 by TdFf indicated their antioxidative potential. Incubation of EAC/DLA tumor cells with TdFf showed a concentration-dependent cytotoxic effect, and the extract killed 50% of EAC/DLA tumor cells at a concentration of 80 μg of TdFf. Coadministration of TdFf with EAC/DLA-induced mice showed a significant increase in the liver enzymic and nonenzymic antioxidants and significant decrease in the serum liver marker enzymes to prove the in vivo antioxidative and antitumor activity of TdFf. It was also confirmed by the histopathology of the liver., Conclusions: It may be concluded that the flavonoid fractions of Td possess considerable antioxidative and antitumorigenic activity against the tested DLA/EAC in both in vitro and in vivo system., Competing Interests: None

Continued interest in bioactive alkaloids led to the isolation of four undescribed alkaloids along with 74 known ones from the aerial parts of Tabernaemontana bufalina Lour. The structures of the yet undescribed alkaloids were elucidated based on NMR, IR, UV, MS and CD spectroscopic data and X-ray crystal diffraction and, according to the plant source, named as taberhaines A-D (1-4). The known compounds comprised of 66 monoterpenoid indole, three carboline and five isoquinoline alkaloids. Among them, the known apparicine inhibited significantly the activity of xanthine oxidase, which plays an important role for gout, with an IC 50 value of 0.65 μM, compared to the standard drug allopurinol (IC 50  = 0.60 μM)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Two new sarpagine-type indole alkaloids (1 and 2), together with five known alkaloids; 12-methoxy-4-methylvoachalotine (3), 16-demethoxycarbonylvoacamine (4), isositsirikine (5), affinisine (6), affinine (7), were isolated from the bark of Tabernaemontana macrocarpa Jack. The structures of these alkaloids were determined based on spectroscopic data, chemical correlation, and comparison with the literature. 16-Demethoxycarbonylvoacamine (4) showed antiplasmodial activities against Plasmodium falciparum 3D7 and cytotoxic activities against human cell line, HepG2 cells.

Plant compounds have been identified as new drug prototypes. In this line, this work aimed to isolate the indole alkaloid affinisine from Tabernaemontana catharinensis and test its antitumor activity. The alkaloid was isolated by silica gel open column chromatography from the ethanolic extract of the stem of T. catharinensis. Afterwards, this molecule was characterized by high-resolution mass spectrometry and nuclear magnetic resonance. In the next step, the cytotoxicity of the compound was tested against human melanoma cell lines (A375, WM1366 and SK-MEL-28) and a normal skin cell line (CCD-1059Sk) using a MTT (3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cells treated with affinisine were evaluated by flow cytometry to analyze apoptosis and the induction of cell cycle arrest, to evaluate the dead mechanism. The metabolite was isolated in a 0.2% yield relative to the extract. Cytotoxic activity of the molecule was observed at 48 h, resulting in considerable growth inhibition rates in melanoma cells, especially in WM1366, which had the lowest IC 50 (32.86 ± 2.54 µg/mL). The apoptosis rate was lower in A375 (56.66 and 86.71% with 57 and 65 µg/mL, respectively). Moreover, affinisine was able to significantly induce cell cycle arrest in different phases in the A375 and WM1366 cell lines. However, in SK-MEL-28 cells, cycle arrest was not observed. In summary, this compound significantly decreased the viability of tumor cells in a dose- and time-dependent manner for all evaluated lineages, reduced cell viability by the apoptosis mechanism and presented prominent activities of cell cycle arrest. In this way, the use of antineoplastic agents is among the most widely used therapeutic measures for the control and treatment of cancer. Affinisine is a promising prototype in the search for new drugs to treat cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

(-)-Ibogaine and (-)-voacangine are plant derived psychoactives that show promise as treatments for opioid addiction. However, these compounds are produced by hard to source plants, making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (-)-voacangine, and de-esterified voacangine, which is converted to (-)-ibogaine by heating, enabling biocatalytic production of these compounds. Notably, (-)-ibogaine and (-)-voacangine are of the opposite enantiomeric configuration compared to the other major alkaloids found in this natural product class. Therefore, this discovery provides insight into enantioselective enzymatic formal Diels-Alder reactions.

Three monoterpenoid indole alkaloids (MIAs), tabernabovines A-C ( 1 - 3 ), were isolated from Tabernaemontana bovina. They were elucidated by spectroscopic data and computational calculations. Unlike precursors of MIAs, strictosidine and alstrostine A, alkaloid 1 consists of tryptamine and secologanin in a 2:1 ratio. Alkaloid 2 is a cage compound, and 3 possesses a bridged ring. Tabernabovine A exhibited inhibitory activity against NO production with IC 50 44.1 μM compared to l-NMMA with IC 50 of 48.6 μM.

Hemostasis is a tightly regulated process which maintains a fluid state of blood within the vasculature and provides thrombotic response upon tissue injury. Various scientific studies have implicated the role of plant latex proteases in hemostasis using in vitro experiments. However, in vivo models substantiate their role in hemostasis. Therefore, in the present study, the effect of plant latex thrombin-like proteases (PTLPs) on hemostasis was investigated systematically using mice tail bleeding as a preclinical model. In this direction, latex protease fractions (LPFs), which showed potent thrombin-like activity, were selected as they act directly on fibrinogen to form clot and quickly stop bleeding. Thrombin-like activity was exhibited mainly by cysteine proteases. Calotropis gigantea, Carica papaya, Jatropha curcas, Oxystelma esculentum, Tabernaemontana divaricata, and Vallaris solanacea LPFs and papain from C. papaya latex significantly reduced bleeding on a topical application in normal and aspirin administered mice. In addition, PTLPs accelerated the clotting of factor VIII deficient plasma, while, papain brought back the clotting time to normal levels acting like a bypassing agent. Further, papain failed to show activity in the presence of specific cysteine protease inhibitor iodoacetic acid; confirming protease role in all the activities exhibited. At the tested dose, PTLPs except C. gigantea did not show toxicity. Further, structural and sequence comparison between PTLPs and human thrombin revealed structural and sequence dissimilarity indicating their unique nature. The findings of the present study may open up a new avenue for considering PTLPs including papain in the treatment of bleeding wounds., (© 2019 Wiley Periodicals, Inc.)

Two new monoterpenoid indole alkaloids, tabervarines A ( 1 ) and B ( 2 ), along with seven known monoterpenoid indole alkaloids, were isolated from the methanol extract of the twigs and leaves of Tabernaemontana divaricata. The structures including the absolute configurations of the new alkaloids were elucidated based on MS, NMR, and ECD calculation. The in vitro cytotoxic activities of the isolated alkaloids against several human cancer cell lines were also evaluated.

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., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Four unprecedented yellow alkaloids named as taberbovines A-D (1-4) were isolated from stems of Tabernaemontana bovina Lour. Their structures were elucidated by the comprehensive spectroscopic data, computational chemistry, and X-ray crystal diffraction. Alkaloids 1-4 possessed a unique 6/6/5/6/5 ring system and were assigned to monoterpenoid quinolines. Biosynthetically, the isolated alkaloids may be derived from Aspidosperma-type alkaloid by oxidation and rearrangements. Taberbovines A-D exhibited the good inhibitory activities of formation NO in LPS induced RAW264.7 macrophages.

Taberniacins A (1) and B (2), new indole alkaloids, were isolated from the stems of Tabernaemontana divaricata (Apocynaceae). Structure elucidation of 1 and 2 was based on spectroscopic methods and total synthesis. Each alkaloid showed vasorelaxant activity against phenylephrine-induced contraction of isolated rat aorta.

Examination of the EtOH extract of the leaves of the Malayan Tabernaemontana corymbosa resulted in the isolation of four new (1-4) and two known bisindole alkaloids (5, 6) of the Aspidosperma- Aspidosperma type. The structures of these alkaloids were determined based on analysis of the spectroscopic data (NMR and HRESIMS). X-ray diffraction analyses of the related bisindole alkaloids conophylline (5) and conophyllinine (6) established the absolute configurations. Treatment of the bisindole alkaloid conophylline (5) with benzeneselenic anhydride gave, in addition to the known bisindole polyervinine (7) previously isolated from another Malayan Tabernaemontana, another bisindole product, 8, an isolable tautomer of 7. X-ray diffraction analyses yielded the absolute configurations of both bisindoles and in addition showed that polyervinine (7) exists primarily as the neutral dione structure. The bisindoles (1-8) and the related conophylline-type bisindoles (9-13) showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, A549, HT-29, and HCT 116 cells, with IC 50 values for the active compounds in the 0.01-5 μM range.