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Goniomitine is of the aspidosperma alkaloid family, with an angularly fused tetracyclic skeleton housing an all-carbon quaternary carbon chiral center alongside an aminal functional group. This natural product has garnered attention as a synthetic target due to its intriguing molecular architecture and anti-proliferative activity in recent years. Following the first synthesis of (-)-goniomitine by Takano in 1991, synthetic chemists have developed various methods. This review provides an overview of the methodologies used in the synthesis of goniomitine in racemic and enantiopure forms via divergent construction indole framework, indole functionalization, and the integrated oxidation/reduction/cyclization (iORC) sequence from 1991 to 2023., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

A new dimeric indole alkaloid, vincazalidine A consisting of an aspidosperma type and a modified iboga type with 1-azatricyclo ring system consisting of one azepane and two piperidine rings coupled with an oxazolidine ring was isolated from Catharanthus roseus, and the structure including absolute stereochemistry was elucidated on the basis of spectroscopic data as well as DP4 statistical analysis. Vincazalidine A induced G2 arrest and subsequent apoptosis in human lung carcinoma cell line, A549 cells., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Ethnopharmacological Relevance: Aspidosperma nitidum Benth (Apocynaceae) is a tree found in Brazil especially in the Amazonia region, known as "carapanaúba", being used by indigenous and cabloco population in folk medicine in the treatment of malaria, leprosy, rheumatism, cancer, diabetes and inflammatory disorders. However, there are no scientific reports, up to now, to evidence its popular use as anti-inflammatory and healing agent., Aim of the Study: This study aimed to isolate indole alkaloids, as well as investigate the safety, anti-inflammatory and healing properties of hydroethanol extract from the stem barks of Aspidosperma nitidum Benth (An)., Material and Methods: The compounds were isolated using diverse chromatographic methodologies and the structures were determined by extensive spectroscopic analyses. The safety was evaluated in vitro through 3-methyl-[4-5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay using murine fibroblast (3T3) and monkey kidney (Vero E6) cell lines and by the hemolytic assay, as well as, in vivo, through acute toxicity model, which the mice received a single dose of 2000 mg/kg of An, by intra-gastric (i.g.) route, and behavioral, hematological and biochemical parameters were evaluated. The anti-edematogenic effect was monitored through carrageenan-induced paw edema model, in which the rodents were treated with 50, 100 and 200 mg/kg of An by i. g., the percentage of edema (0-4 h), myeloperoxidase (MPO) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) levels were quantified. The anti-inflammatory activity was demonstrated through the zymosan-air-pouch model, in which the animals were treated with 50, 100 and 200 mg/kg of An by i. g, and the leukocytes number, MPO, total protein and cytokines levels were determined. In addition, the healing potential was evaluated through a skin wound model, in which the mice received 50, 100 and 200 mg/mL of An in wound area, and the wound skins were photographed and the area calculated., Results: In total, five compounds were isolated in the An, being a new 8,9-dinorneolignan glucoside and four known indole alkaloids. The MTT and hemolytic assays, in all concentrations of the extract, demonstrated not be cytotoxic. Acute toxicity model also evidenced no sign of toxicity or significant changes on the behavior, biochemical and hematological parameters after use of the extract. In the edematogenic model, the An reduced significantly the percentage of edema, as well as, the MPO and pro-inflammatory cytokines levels. The same form, An revealed to be efficient in decreasing the leukocytes migration (mainly polymorphonuclears), total proteins, MPO and cytokines concentrations in the zymosan-air-pouch assay. Moreover, the An revealed a healing effect, reducing the area of the skin wound., Conclusion: Ours results evidence in the first time, the anti-inflammatory and healing property of An, justifying its use in traditional medicine. Moreover, include cytotoxicity in vitro and acute toxicity in vivo tests, which indicate the safety of use of the extract., 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.)

We report here a homo-Mannich reaction of cyclopropanol with an iminium ion, generated by an asymmetric allylic dearomatization of indole, to construct a tricyclic hydrocarbazole core, which is shared by a variety of monoterpenoid indole alkaloids across families. Through this approach, an all-carbon quaternary stereogenic center as well as an allyl and a ketone group were installed. Using this functionalized hydrocarbazole as the structural platform, D ring and E rings of different sizes (i.e., five-, six-, and seven-membered) were successively or simultaneously assembled, leading to a collective asymmetric synthesis of seven alkaloids belonging to the ibophyllidine, Aspidosperma, Kopsia, and Melodinus alkaloid families., (© 2023 Wiley-VCH GmbH.)

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.)

The alkaloid Aspidocarpine was isolated from the bark of Aspidosperma desmanthum. Its structure was elucidated by the spectral data of 1H and 13C-NMR (1D and 2D) and high-resolution mass spectrometry (HRESIMS). The antihypertensive activity was investigated by intravenous infusion in Wistar rats. This alkaloid significantly reduced (p < 0.05) the systolic, median, and diastolic blood pressures of rodents, without causing motor incoordination and imbalance in the rotarod test. The results indicate that the alkaloid Aspidocarpine exerts its antihypertensive activity without causing sedation or the impairment of motor functions.

This study evaluated the morphological changes caused by fractions and subfractions, obtained from barks of Aspidosperna nitidum, against L. (L.) amazonensis promastigotes. The ethanolic extract (EE) obtained through the maceration of trunk barks was subjected to an acid-base partition, resulting the neutral (FN) and the alkaloid (FA) fractions, and fractionation under reflux, yielded hexane (FrHEX), dichloromethane (FrDCL), ethyl acetate (FrACoET), and methanol (FrMEOH) fractions. The FA was fractionated and three subfractions (SF5-6, SF8, and SF9) were obtained and analyzed by HPLC-DAD and 1 H NMR. The antipromastigote activity of all samples was evaluated by MTT, after that, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) for the active fractions were performed. Chromatographic analyzes suggest the presence of alkaloids in EE, FN, FA, and FrDCL. The fractionation of FA led to the isolation of the indole alkaloid dihydrocorynantheol (SF8 fractions). The SF5-6, dihydrocorynantheol and SF-9 samples were active against promastigotes, while FrDCL was moderately active. The SEM analysis revealed cell rounding and changes in the flagellum of the parasites. In the TEM analysis, the treated promastigotes showed changes in flagellar pocket and kinetoplast, and presence of lipid inclusions. These results suggest that alkaloids isolated from A. nitidum are promising as leishmanicidal., (© 2022. The Author(s).)

We demonstrated here a series of Aspidosperma terpenoid alkaloids can be quickly prepared using semisynthesis from naturally sourced tabersonine, featuring multiple oxygen-based substituents on the indole ring such as hydroxy and methoxy groups. This panel of complex compounds enabled the exploration of indole modifications to optimize the indole alkaloids' anticancer activity, generating lead compounds ( e.g. , with C15-hydroxy, C16-methoxy, and/or C17-methoxy derivatizations) that potently inhibit cancer cell line growth in the single-digit micromolar range. These results can help guide the development of Aspidosperma terpenoid alkaloid therapeutics. Furthermore, this synthetic approach features late-stage facile derivatization on complex natural product molecules, providing a versatile path to indole derivatization of this family of alkaloids with diverse chemical functionalities for future medicinal chemistry and chemical biology discoveries.

We report the first total synthesis of (-)-kopsifoline A and (+)-kopsifoline E. Our synthetic strategy features a biogenetically inspired regioselective C17-functionalization of a versatile intermediate containing the pentacyclic core of aspidosperma alkaloids. The vinylogous urethane substructure of this intermediate affords (-)-kopsifoline D via C3-C21 bond formation under the Mitsunobu reaction conditions, while it enables selective C17-functionalization en route to (-)-kopsifoline A and (+)-kopsifoline E.

This study investigated the acute and subacute toxicity of the ethanolic extract (EE) and alkaloid fraction (FA) from A. nitidum. The EE was obtained from trunk bark with ethanol, FA was obtained from the fractionation of EE. To test the acute toxicity, mice were divided into four groups, and the negative controls received water or aqueous solution of dimethyl sulfoxide, whereas the others received EE or FA (2000 mg/kg, orally, single dose). The same controls were used in the subacute trial. However, the animals were treated for 28 days, and the dose used was 1000 mg/kg per day of EE and FA. Daily clinical evaluations of the animals were performed. At the end of the experiment, hematological, biochemical, and histopathological assessments (liver, lung, heart, and kidney) were performed. In the acute and subacute toxicity studies, mice treated with EE and FA did not show any clinical changes, there were no changes in weight gain, hematological and biochemical parameters compared to the control groups (p > 0.05). In the histopathological examination, there was no abnormality in the organs of the treated animals. Therefore, EE and FA did not produce toxic effects in mice after acute and subacute treatment., (© 2021. The Author(s).)

Quorum sensing (QS) represents a major target for reducing bacterial pathogenicity and antibiotic resistance. This study identifies bergamot and aspidosperma as new potential sources of anti-QS agents. We investigated the anti-QS activity of plant materials on both Chromobacterium violaceum and Pseudomonas aeruginosa. Initially, we determined the minimum inhibitory concentrations (MICs) of plant materials using a broth microdilution method. Subsequently, we tested the effect of sub-MIC concentrations on QS-regulated traits and virulence factors production in test bacteria. Results revealed that bergamot and aspidosperma inhibited the ability of C. violaceum to produce violacein. Other QS-controlled phenotypes of C. violaceum, namely chitinolytic activity, motility, and biofilm formation, were also reduced by both plant materials. Moreover, QS-linked traits of P. aeruginosa were also reduced. Bergamot inhibited swarming but not swimming motility, while aspidosperma diminished both motility types in P. aeruginosa. Both plant materials also demonstrated antibiofilm activity and inhibited the production of protease and pyocyanin in P. aeruginosa. Furthermore, we tested the anti-QS effect of plant materials on the transcriptional level using RT-qPCR. Bergamot dramatically downregulated the C. violaceum autoinducer synthase gene cviI and the vioB gene involved in violacein biosynthesis, confirming the phenotypic observation on its anti-QS activity. Aspidosperma also reduced the expression of cviI and vioB but less drastically than bergamot. In P. aeruginosa, downregulation in the transcripts of the QS genes lasI, lasR, rhlI, and rhlR was also achieved by bergamot and aspidosperma. Therefore, data in the present study suggest the usefulness of bergamot and aspidosperma as sources of antivirulence agents., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

A concise formal synthesis of (±)-aspidospermidine via Stork's intermediate, which could be used as a divergent synthesis of Aspidosperma alkaloids, was achieved by employing a ring-opening cyclization of spirocyclopropane with amine followed by a regioselective intramolecular/intermolecular alkylation sequence. Stork's intermediate was synthesized in only six steps from a simple starting material, 1,3-cyclohexanedione, and was converted into (±)-aspidospermidine. To the best of our knowledge, this synthesis of Stork's intermediate involves the least number of steps to date. Furthermore, no protecting groups were used during this synthesis.

The first asymmetric total synthesis of aspidosperma alkaloid (+)-winchinine B was achieved in 12 steps from commercially available materials. A new synthetic strategy which features an efficient aza-Michael addition, a ruthenium-catalyzed transfer dehydrogenation, and an intramolecular palladium-catalyzed oxidative coupling was adopted to install the ABC tricycle system. A one-pot process involving carbonyl reduction/iminium formation/intramolecular conjugate addition developed by our group was utilized to construct the D ring moiety.

In this work, the antifouling activity of five alkaloids, isolated from trees of the Atlantic rainforest, was studied. The tested alkaloids were olivacine (1), uleine (2) and N-methyltetrahydroellipticine (3) from Aspidosperma australe ('yellow guatambú') and the furoquinoline alkaloids kokusaginine (4) and flindersiamine (5) from Balfourodendron riedelianum ('white guatambú'). All these compounds can be isolated from their natural sources in high yields in a sustainable way. The five compounds were subjected to laboratory tests (attachment test of the mussel Mytilus edulis platensis) and field trials, by incorporation into soluble matrix paints, and 45 days of exposure of the painted panels in the sea. The results show that compound 3 is a very potent antifoulant, and that compounds 4 and 5 are also very active, while compounds 1 and 2 did not show any significant antifouling activity. These results open the way for the development of environmentally friendly antifouling agents, based on abundant and easy-to-purify compounds that can be obtained in a sustainable way., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Monoterpenoid indole alkaloids are the major class of tryptamine-derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis , a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids ( 1 ⁻ 14 ) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3 , 6 , 9 , and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC 50 values ranging from 0.5⁻0.9 μM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or β-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3 , 4 , 6 , 7 , and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site.

Ethnopharmacological Relevance: Species of Aspidosperma are known popularly as "peroba, guatambu, carapanaúba, pau-pereiro" and "quina". The genus can be found in the Americas, mainly between Mexico and Argentina. Many species of Aspidosperma are used by the population in treating cardiovascular diseases, malaria, fever, diabetes and rheumatism. The phytochemical aspects of the species of the genus Aspidosperma have been studied extensively. The monoterpene indole alkaloids are the main secondary metabolites in Aspidosperma species, and about 250 of them have been isolated showing a considerable structural diversity. Several of them have showed some important pharmacological activities. Aspidosperma subincanum Mart. and Aspidosperma tomentosum Mart. (Apocynaceae) are Brazilian species widely used by the population to treat diabetes mellitus, hypercholesterolemia. The pharmacological activities of both species have been investigated and the biological properties described can be related to their isolated indole alkaloids. However, more pharmacological studies are needed in order to justify the use of these species in folk medicine. In this review, we present reports mainly focused on chemical and biological studies and their relationship with the ethnopharmacological use of both Aspidosperma species., Aim of the Study: The aim of this review is to present their ethnopharmacological use as correlated to their biological activities as described for the extracts and isolated compounds from Aspidosperma subincanum Mart. and Aspidosperma tomentosum Mart. In addition, some aspects related to the biosynthetic pathways are discussed, also NMR assignments and some synthesis information about indole alkaloids from both Aspidosperma species are included., Material and Methods: The bibliographic search was made in theses and dissertations using some databases such as NDLTD (Networked Digital Library of Theses and Dissertations), OATD (Open Access Theses and Dissertations) and Google Scholar. More data were gathered from books, Brazilian journals and articles available on electronic databases such as, Google Scholar, PubChem, Scifinder, Web of Science, SciELO, PubMed and Science Direct. Additionally, the Google Patents and Espacenet Patent Search (EPO) were also consulted. The keywords Aspidosperma, A. subincanum, A. tomentosum, indole alkaloids were used in the research. The languages were restricted to Portuguese, English and Spanish and references were selected according to their relevance., Results: A. subincanum Mart. and A. tomentosum Mart. (Apocynaceae) are Brazilian species widely used by the population to treat a few diseases. Extracts and isolated compounds of both species have shown antitumor and antimalarial activities. The antitumor activity of isolated compounds has been extensively studied. However, the antiplasmodial activity needs to be investigated further as well as the anti-inflammatory, anti-hyperlipidemic and anorexigenic activities. From A. subincanum twenty-one indole alkaloids were isolated and some of them have been extensively studied. From the leaves and bark of A. tomentosum four alkaloids and one flavonoid were isolated. Furthermore, CG-MS analysis of seeds, branches, leaves and arils identified nine indole alkaloids. Stemmadenine has been proposed as a precursor of indole alkaloids obtained from some species of Aspidosperma. Many of the biosynthetic steps have been characterized at the enzymatic level and appropriate genes have been identified, however, other steps have yet to be investigated and they are still controversial. Some isolated alkaloids from A. subincanum and A. tomentosum were identified only by mass spectrometry. In many cases, their NMR data was either not available or was incomplete. The described meta-analysis of the available NMR data revealed that the chemical shifts belonging to the indole ring might be used to characterize this class of alkaloids within complex matrices such as plant extracts. The biological activities and the structural complexity of these compounds have stimulated the interest of many groups into their synthesis. In this review, some information about the synthesis of indole alkaloids and their derivatives was presented., Conclusions: A. subincanum and A. tomentosum are used by the population of Brazil to treat many diseases. A few biological activities described for the extracts and isolated compounds of both species are in agreement with the ethnopharmacological use for others species of Aspidosperma, such as, antimalarial, the treatment of diabetes and other illnesses. These species are sources of leading compounds which can be used for developing new drugs. In addition, other biological activities reported and suggested by ethnopharmacological data have yet to be investigated and could be an interesting area in the search for new bioactive compounds., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aspidospermidine, vincadifformine, 1,2-dehydroaspidospermidine, goniomitine, and quebrachamine, five Aspidosperma alkaloids distributed within three structurally diverse topologies, were synthesized from a single molecular scaffold, namely indole-valerolactam 6. This common intermediate can be divergently manipulated, through the incorporation of conformational and electronic constraints that influence the chemo-selectivity of the iminium ion derived therefrom, between three different reaction paths: N(1) vs. C(3) cyclization (indole numbering) vs. over-reduction. Moreover, a catalytic carbene insertion for direct C(3)-H indole functionalization is reported for the first time in an approach to goniomitine (4), and a following tandem ester reduction/iminium generation/cyclization secured its tetracyclic system. The development of a highly diastereoselective one-pot hemi-reduction/cyclization/deprotection process to obtain a cis-pyridocarbazole directly allowed the synthesis of pentacyclic Aspidosperma alkaloids 1, 2, and 3.

Background: Several species of Aspidosperma plants are referred to as remedies for the treatment of malaria, especially Aspidosperma nitidum. Aspidosperma pyrifolium, also a medicinal plant, is used as a natural anti-inflammatory. Its fractionated extracts were assayed in vitro for activity against malaria parasites and for cytotoxicity., Methods: Aspidosperma pyrifolium activity was evaluated against Plasmodium falciparum using extracts in vitro. Toxicity towards human hepatoma cells, monkey kidney cells or human monocytes freshly isolated from peripheral blood was also assessed. Anti-malarial activity of selected extracts and fractions that presented in vitro activity were tested in mice with a Plasmodium berghei blood-induced infection., Results: The crude stem bark extract and the alkaloid-rich and ethyl acetate fractions from stem extract showed in vitro activity. None of the crude extracts or fractions was cytotoxic to normal monkey kidney and to a human hepatoma cell lines, or human peripheral blood mononuclear cells; the MDL 50 values of all the crude bark extracts and fractions were similar or better when tested on normal cells, with the exception of organic and alkaloidic-rich fractions from stem extract. Two extracts and two fractions tested in vivo caused a significant reduction of P. berghei parasitaemia in experimentally infected mice., Conclusion: Considering the high therapeutic index of the alkaloidic-rich fraction from stem extract of A. pyrifolium, it makes the species a candidate for further investigation aiming to produce a new anti-malarial, especially considering that the active extract has no toxicity, i.e., no mutagenic effects in the genototoxicity assays, and that it has an in vivo anti-malarial effect. In its UPLC-HRMS analysis this fraction was shown to have two major components compatible with the bisindole alkaloid Leucoridine B, and a novel compound, which is likely to be responsible for the activity against malaria parasites demonstrated in in vitro tests.

Three new bisindole alkaloids, bisleuconothines B-D (1-3), were isolated from the bark of Leuconotis griffithii. Their structures were elucidated by 1D and 2D NMR spectroscopy and DFT calculations. Bisleuconothine B (1) is the first monoterpene indole alkaloid dimer featuring bridges between both C-16-C-10' and C-2-O-C-9'. All compounds were deemed noncytotoxic (IC 50 > 10 μM) when tested against A549 human lung adenocarcinoma cells.

Species of Aspidosperma are traditionally used to treat malaria, leishmaniasis, microbial, and inflammatory diseases. Aspidosperma subincanum Mart. known as "guatambu" is used in Brazilian traditional medicine to treat diabetes, hypercholesterolemia, and digestive diseases. Its tonic properties have been employed by the indigenous populations to stimulate the circulatory and genitourinary tracts and to improve respiratory function as well as to relieve spasms and to reduce fever. The species is known to contain antitumoural and antimalarial indole alkaloids. In the present study, various less explored biological activities of extracts from leaves and branches of A. subincanum were investigated, that is, inhibition of acetylcholinesterase as well as antioxidant and antibacterial activity. Twenty-one known indole alkaloids from this species were targeted for predicting the inhibition of acetylcholinesterase, and their biological activities were collected from the literature. Through in silico the prediction, the indole alkaloids uleine and derivatives demonstrated a strong probability of being able to inhibit the acetylcholinesterase enzyme, as well as the olivacine derivatives 3,4-dihydroolivacine and N-methyl-tetrahydro-olivacine (guatambuine), and the subincanadines C and E. Indeed, the extracts of A. subincanum showed acetylcholinesterase inhibitory activity, antioxidant activity in the lipid peroxidation assay, and antimicrobial activity against Staphylococcus aureus ATCC 25923, and their pharmacological properties should be explored further., (© 2018 John Wiley & Sons, Ltd.)

Covering: up to the end of 2017 Enantioselective Pd-catalyzed allylic alkylations of prochiral enolates represent a powerful tool for the construction of all-carbon quaternary stereocenters. This review describes the emergence of such reactions as strategic linchpins that enable efficient, stereocontrolled syntheses of Aspidosperma and related monoterpene indole alkaloids.

Objectives: Aspidosperma species are used for several diseases, especially for malaria in Brazil. Although the genus is object of pharmacological studies, almost none are found on Aspidosperma pyrifolium. We investigate neuroprotective, antioxidant and anti-inflammatory properties of the APSE-Aq fraction (benzoic acid glycosylated derivative) on Parkinson's disease model., Methods: Male Wistar rats were subjected to a 6-hydroxydopamine injection into the right striatum and treated or not with APSE-Aq (100 or 200 mg/kg, p.o.). The sham-operated group was injected with saline. Two weeks later, animals were subjected to behavioural, neurochemical and immunohistochemical evaluation. The data were analysed by ANOVA and Tukey test., Key Findings: The APSE-Aq-treated group shows a partial recovery of behavioural changes as compared with the untreated-6-hydroxydopamine group. A partial recovery was also observed in nitrite contents and lipid peroxidation. APSE-Aq treatments significantly reversed decreases in striatal dopamine and metabolites in the untreated 6-hydroxydopamine group. Immunostainings for markers as tyrosine hydroxylase and dopamine transporter decreased in the untreated 6-hydroxydopamine group and values recovered after APSE-Aq treatments. Similar data were seen for TNF-alpha., Conclusion: APSE-Aq presents neuroprotective, antioxidant and anti-inflammatory activities. Considering that APSE-Aq is chemically related to salicylic acid, it may act on similar targets., (© 2018 Royal Pharmaceutical Society.)

Ynamides, as versatile synthetic precursors, have attracted much attention from synthetic chemists and sparked the development of a number of methodologies for the construction of various structures. 1H-Pyrrolo[2,3-d]carbazole is a core scaffold of a series of monoterpene indole alkaloids found in Kopsia, Strychnos, and Aspidosperma, for example. In this study, 1H-pyrrolo[2,3-d]carbazole derivatives were synthesized by a Brønsted acid-catalyzed tandem cyclization starting from tryptamine-based ynamides. This strategy prevented Wagner-Meerwein rearrangement by instantaneous intramolecular nucleophilic trapping of the indoleninium to afford a tetracyclic indoline via an in situ-formed enol species induced by the formation of a more stable conjugate diene moiety. The functional group tolerances were investigated by using a series of readily available substrates. A plausible mechanism has been proposed based on the evidence of the capture of the hemiaminal intermediate. Lastly, a Büchi ketone, which is the pivotal intermediate in the synthesis of the indole alkaloid vindorosine, was synthesized by utilizing our newly developed methodology., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Dietary phenolic compounds are plant metabolites with beneficial effects on the central nervous system. Thus, our aim was to identify anti-inflammatory compounds from South American plants on glia, which regulates neuro-immune response. The compounds were extracted from Lantana grisebachii (LG), Aspidosperma quebracho-blanco (AQB), and Ilex paraguariensis (IP) teas and identified by HPLC-DAD-MS. Extracts (0-200 µg/ml) were tested on human T98-G and rat C6 glioma lines. Cellular viability (by the resazurin assay), fatty acid profile (by gas chromatography) and pro-inflammatory interleukin-6 release (IL-6 by ELISA) were determined. Data were analyzed by partial least-square regression to discriminate bioactive compounds. Twenty-one compounds were determined in LG, mainly iridoids, which were linked to ω-3 and ω-6 polyunsaturated fatty acids, but not to IL-6 release. Thirty-one compounds were found in AQB, mostly hydroxybenzoic derivatives, which were positively related to IL-6 release. Twenty-three compounds were identified in IP, including caffeoylquinic derivatives and mainly chlorogenic acid. They increased the ω-7 palmitoleic fatty acid, which was related to IL-6 decrease. These results enhances phytochemical knowledge of widely available plants, and suggest the lipid-related anti-inflammatory activity of IP phenolic compounds, which give nutritional relevance to the tea.

Background: Plant extracts can be obtained to carry bioactive compounds, useful for prevention and treatment of different illnesses. This also supports the intake of teas as functional beverages. Nonetheless, it is incompletely known whether these extracts can act as effective sources and vehicles de phenolic compounds (phenolics/polyphenols) to reach their targets., Objective: To establish whether phytoextract ingestion modified in a sex-dependent manner the phenolic bioavailability and redox response in liver and kidney., Method: BALB/C mice ingested for a month 100 mg/Kg/d of extracts (tea-like) from Aspidosperma quebracho-blanco (AQB), Lantana grisebachii (LG) or Ilex paraguariensis (IP). Then, phenolics, peroxides and nitrites were analyzed by spectrophotometry. Also, phenolic permeation from digested and undigested extracts was evaluated in vitro with a rat jejunum-based assay., Results: Phenolic permeation depended on extract digestion. In males, IP showed a special time course of hepatic phenolics, whereas all extracts decreased renal phenolics at 15 days. Extracts induced hepatic lipoperoxides at 15 days. LG reduced renal hydroperoxides at 15 days and hepatic nitrites at 30 days, whereas AQB and IP reduced renal lipoperoxides and nitrites at 30 days. In females, extracts reduced hydroperoxides, with LG and AQB also reducing lipoperoxides. IP increased renal lipoperoxides at 30 days., Conclusion: IP was a relevant phenolic source. Sex-dependent responses were found in all variables, which should be considered to prevent misleading generalizations in phytodrug bioprospecting.

Background: Chlorpyrifos is an highly toxic pesticide, which can induce immunotoxicity with deleterious effects on health worldwide. On the other hand, American plants can provide derivatives with protective and immunostimulating activity. Thus, plant potential against chlorpyrifos should be assayed., Objective: To identify bioactive aqueous extracts from Lantana grisebachii (LG), Aspidosperma quebracho-blanco (AQ), Peumus boldus (PB), and Ilex paraguariensis (IP), against chlorpyrifos-induced toxicity on female Balb/c splenocytes. Material and method: Splenocytes were treated in vitro for 72 hours with 0-35 µg/mL of chlorpyrifos, 0-100 µg/mL of each extract (LG, AQ, PB, IP), and 0-5 µg/mL of concanavalin A. Then, cellular viability and death (resazurin-based and propidium iodide stainings), hydroperoxides, lipoperoxides (xylenol orange-based assay), ?-glutamyl transpeptidase activity (Szasz method) were measured and analyzed statistically., Results: Chlorpyrifos reduced splenocyte viability in a dose-dependent manner, which was counteracted by AQ and IP, which was less active in concanavalin A-responsive cells (p<0.05). Chlorpyrifos toxicity involved ?-glutamyltranspeptidase induction with a consequent peroxide reduction, whereas AQ and mainly IP antagonized these responses (p<0.05)., Conclusions: The extracts of Ilex paraguariensis and Aspidosperma quebracho-blanco protected splenocytes in vitro against chlorpyrifos. This effect depended on cellular type, given that concanavalin A-responsive cells were more susceptible to this toxic.

Scorpions of the genus Tityus are responsible for the majority of envenomation in Brazil, the Tityus serrulatus species being the most common and dangerous in South America. In this approach, we have investigated the ability of the aqueous extract from the leaves of Aspidosperma pyrifolium in reducing carrageenan-induced inflammation and the inflammation induced by T. serrulatus envenomation in mice. We also evaluated the cytotoxic effects of this extract, using the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl-2H-tetrazolium (MTT) assay and the results revealed that the extract is safe. Analysis by High Performance Liquid Chromatography coupled with Diode Array Detector (HPLC-DAD) and Liquid Chromatography Coupled with Mass Spectrometry with Diode Array Detection (LC-DAD-MS) showed one major chemical component, the flavonoid rutin and phenolics compounds. For in vivo studies in carrageenan-induced peritonitis model, mice received extracts, dexamethasone, rutin or saline, before administration of carrageenan. For venom-induced inflammation model, animals received T. serrulatus venom and were, simultaneously, treated with extracts, antivenom, rutin or saline. The extract and rutin showed a reduction in the cell migration into the peritoneal cavity, and in the same way the envenomated animals also showed reduction of edema, inflammatory cell infiltration and vasodilation in lungs. This is an original study revealing the potential action of A. pyrifolium against inflammation caused by Tityus serrulatus venom and carrageenan, revealing that this extract and its bioactive molecules, specifically rutin, may present potential anti-inflammatory application., Competing Interests: The authors declare no conflict of interest.

The first enantioselective total synthesis of (-)-deoxoapodine is described. Our synthesis of this hexacyclic aspidosperma alkaloid includes an efficient molybdenum-catalyzed enantioselective ring-closing metathesis reaction for the desymmetrization of an advanced intermediate that introduces the C5-quaternary stereocenter. After C21-oxygenation, the pentacyclic core was accessed by electrophilic C19-amide activation and transannular spirocyclization. A biogenetically inspired dehydrative C6-etherification reaction proved highly effective to secure the F-ring and the fourth contiguous stereocenter of (-)-deoxoapodine with complete stereochemical control., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates were used to construct the C20-quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet-Spengler and Bischler-Napieralski cyclization/reduction cascades furnish the cis- and trans-fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)-limaspermidine and (+)-kopsihainanine A., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Biomedical potential of polyphenols lies in their ability to modulate redox balance and the mechanisms involved in the development of chronic noncommunicable diseases., Objective: The aim of this study was to determine the concentration of total polyphenols in different murine organs by assaying analytical techniques of Folin Ciocalteu (FC) and Fast Blue BB (FBBB)., Method: Balb/c female mice (n≥3) received for 15 days 100 mg/kg/d of extract of Lantana grisebachii (LG), Aspidosperma quebracho-blanco (AQB) or Ilex paraguariensis (IP) and control group (treated with water without extract). Polyphenolic concentrations were measured in telencephalon, diencephalon, midbrain, brainstem, cerebellum, spleen, thymus and cardiopulmonary tissue by FC and FBBB methods. Results were compared by ANOVA followed by Tukey test (p<0.05)., Results: FBBB method reported higher detections than FC (4.5 fold in telencephalon, 8.4 in midbrain, 5 in brainstem, 7.2 in spleen, 68.5 in thymus and 4 in cardiopulmonary tissue). Regarding the treatments, the group that received AQB showed to have increased polyphenolic bioavailability in brainstem (p<0.02). With FBBB, a decrease on thymic polyphenol content after treatment with IP was detected (p<0.005). In cerebellum of the groups treated with IP and telencephalon of the control group showed significant differences when these were analyzed with FC (p<0.05, p<0.0035 respectively)., Conclusions: FBBB method showed higher estimations of polyphenolic bioavailability than FC, and this could be related to higher specificity of the technique to react with phenolic compounds.

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.

Examination of the EtOH extract of the Malayan Tabernaemontana corymbosa resulted in the isolation of three new alkaloids, viz., cononuridine (1), an unusual hexacyclic, iboga-derived, monoterpenoid indole characterized by contraction of the tetrahydroazepine C-ring and incorporation of an additional isoxazolidine ring, taberisidine (2), a seco-corynanthean alkaloid, and conofolidine (3), an Aspidosperma-Aspidosperma bisindole that 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, HT-29, and HCT 116 cells. The structures and absolute configurations of 1 and 3 and the absolute configuration of the novel pyridopyrimidine indole alkaloid vernavosine (4) were confirmed by X-ray diffraction analysis. A reasonable biosynthesis route to cononuridine starting from an iboga precursor is presented.

A new approach for the divergent total syntheses of (±)-vincaminorine, (±)-N-methylquebrachamine, (±)-quebrachamine, (±)-minovine and (±)-vincadifformine, each in less than 10 linear steps starting from a single δ-lactam building block, is reported. Key to our route design is the late-stage generation of reactive enamine functionality from stable indole-linked δ-lactams via a highly chemoselective iridium(I)-catalyzed reduction. The efficiently formed secodine intermediates subsequently undergo either a formal Diels-Alder cycloaddition or a competitive Michael addition/reduction to access aspidosperma-type alkaloids in excellent diastereoselectivities. Product selectivity could be controlled by changing the indole N-protecting group in the reductive cyclization precursors. An asymmetric variant of this synthetic strategy for the synthesis of (+)-20-epi-ibophyllidine is also described., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A short synthetic sequence leading to the formation of the C,D,E-ring subunit of the Aspidosperma alkaloids is reported. This route is based on a ring fragmentation/intramolecular azomethine ylide 1,3-dipolar cycloaddition reaction sequence that gives the desired tricyclic product as a single diastereomer. A γ-amino-β-hydroxy-α-diazo carbonyl compound is shown to fragment in the presence of a Lewis acid to give an iminium product that can be directly reduced to the corresponding amine.

A novel approach to prepare the core structure of Aspidosperma and Strychnos alkaloids is described. The strategy is based on a cyclization cascade involving the formation of quaternary carbon center followed by trapping of the radical intermediate by an aryl azide to build the 5-membered ring of the pyrrolocarbazole system. This reaction is run with triethylborane without the need for any hydrogen atom donor such as a tin hydride or tris(trimethylsilyl)silane, and it furnishes the tetracyclic framework as a single diastereomer. The influence of different N-protecting groups on the starting iodoacetamide has been examined.

This chapter covers the literature on bisindole alkaloids consisting of monoterpenoid indoles, published up to June 2015. Bisindole alkaloids isolated from plants belonging to the families Apocynaceae and Loganiaceae, including Iboga-vobasine type, Aspidosperma-Aspidosperma type, eburnan-Aspidosperma type, Strychnos-Strychnos type, macroline-macroline type, and so on, are described. Some recent syntheses of monoterpenoid bisindole alkaloids are outlined as well., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Several species of Aspidosperma plants are used to treat diseases in the tropics, including Aspidosperma ramiflorum, which acts against leishmaniasis, an activity that is experimentally confirmed. The species, known as guatambu-yellow, yellow peroba, coffee-peroba and matiambu, grows in the Atlantic Forest of Brazil in the South to the Southeast regions. Through a guided biofractionation of A. ramiflorum extracts, the plant activity against Plasmodium falciparum was evaluated in vitro for toxicity towards human hepatoma G2 cells, normal monkey kidney cells and nonimmortalised human monocytes isolated from peripheral blood. Six of the seven extracts tested were active at low doses (half-maximal drug inhibitory concentration < 3.8 µg/mL); the aqueous extract was inactive. Overall, the plant extracts and the purified compounds displayed low toxicity in vitro. A nonsoluble extract fraction and one purified alkaloid isositsirikine (compound 5) displayed high selectivity indexes (SI) (= 56 and 113, respectively), whereas compounds 2 and 3 were toxic (SI < 10). The structure, activity and low toxicity of isositsirikine in vitro are described here for the first time in A. ramiflorum, but only the neutral and precipitate plant fractions were tested for activity, which caused up to 53% parasitaemia inhibition of Plasmodium berghei in mice with blood-induced malaria. This plant species is likely to be useful in the further development of an antimalarial drug, but its pharmacological evaluation is still required.

Vegetable infusions (VI) are one of the main phenolic sources for humans. They may act as antioxidants in the central nervous system, but data about their effect are insufficient. The main objective of the study was to determinate the effects of oral VI of Argentinean plants on phenolic concentration and redox homeostasis in different murine encephalic regions. Redox changes (peroxides -HP-, anion superoxide -SO- and γ-glutamyltranspeptidase activity) and tissue phenolics were assessed in Balb/c mice of both sexes treated with the following VI extracts: Lantana grisebachii Seckt. var. grisebachii (Verbenaceae) (LG), Aspidosperma quebracho-blanco Schltdl. (Apocynaceae) (AQB), and Ilex paraguariensis A. St.-Hil. (Aquifoliaceae) (IP). Brain (telencephalon and diencephalon), midbrain, brainstem, and cerebellum were studied (analysis of variance, P < 0.05). A redox homeostasis depending on an appropriate phenolic balance was detected after marker analysis. Under situations without exogenous challenges, the excessive or deficient levels were deleterious on each region. This finding was confirmed independently of the utilized phytoextracts. LG and AQB caused such phenolic imbalance and triggered oxidative stress. IP group showed region-specific differential redox effects. Overall, the last extract exhibited the best redox profile when the complete encephalon was analyzed. Since this plant has sanitary impact due to its high human intake, new studies about it are warranted.

The first mechanistic investigation of electrophilic amide activation of α,α-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, (1)H, (13)C, and (19)F NMR in our interrupted Bischler-Napieralski-based synthetic strategy to the aspidosperma alkaloids, including a complex tetracyclic diiminium ion, is discussed. The reactivity of a wide range of pyridines with trifluoromethanesulfonic anhydride was systematically examined, and characteristic IR absorption bands for the corresponding N-trifluoromethanesulfonylated pyridinium trifluoromethanesulfonates were assigned. The reversible formation of diiminium ether intermediates was studied, providing insight into divergent mechanistic pathways as a function of the steric environment of the amide substrate and stoichiometry of reagents. Importantly, when considering base additives during electrophilic amide activation, more hindered α-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation.

Here we report the discovery of a cytochrome P450 that is required for the biosynthesis of vindoline, a plant-derived natural product used for semi-synthesis of several anti-cancer drugs. This enzyme catalyzes the formation of an epoxide that can undergo rearrangement to yield the vincamine-eburnamine backbone, thereby providing evidence for the long-standing hypothesis that the aspidosperma- and eburnamine-type alkaloids are biosynthetically related.

The Aspidosperma genus (Apocynaceae) represents one of the largest sources of indole alkaloids widely associated with cardiovascular effects. Aspidosperma fendleri, a plant found mainly in Venezuela, has a single phytochemical report in which is revealed the presence of alkaloids in its seeds. This study explored the cardiovascular effects of an ethanolic extract of A. fendleri leaves (EEAF) in spontaneously hypertensive rats (SHR) and its potential bioactive compounds. Using bioguided fractionation, fractions and pure compounds were intravenously administered to SHR and their effects on mean arterial blood pressure (MABP) and heart rate (HR) monitored over time. EEAF induced hypotensive and bradycardic effects as shown by significant reductions in mean arterial blood pressure (MABP) and heart rate (HR), respectively. Bioactivity-guided fractionation led to the isolation of a mixture of two known isomeric triterpenoid glycosides identified by spectral evidence as quinovic acid 3-O-β-rhamnopyranoside and quinovic acid 3-O-β-fucopyranoside. This mixture of triterpenoid saponins induced reductions in MABP and HR similar to those induced by propranolol. Together, these findings indicate that the two quinovic acid glycosides are responsible for the hypotensive and bradycardic effects which suggest their potential use in cardiovascular therapy.

Plants belonging to the genus Aspidosperma, a member of the family Apocynaceae, provide a rich source of β-carboline alkaloids, which makes them potentially poisonous. However, some of these alkaloids possess antitumor and antimicrobial activity. The present review is a survey of the β-carboline alkaloids and shows that they comprise of a diverse array of structural modifications.

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (-)-mehranine and (+)-(6S,7S)-dihydroxy-N-methylaspidospermidine. A late-stage dimerization of (-)-mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (-)-methylenebismehranine., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Argentinian native plants Aspidosperma quebracho-blanco, Lantana grisebachii and Ilex paraguariensis are known to have antiinflammatory and antioxidant properties. We demonstrated it in vivo by the redox changes in murine hemolymphatic tissues after infusive extract intake of these plants as revealed in organic trophism, tissue phenolics, hydroperoxides, superoxide, nitrites and gamma-glutamyltranspeptidase in thymus, blood and spleen. A. quebracho-blanco reduced hydroperoxidation in blood and spleen of both sexes, with gamma-glutamyltranspeptidase negativization in lymphatic organs and thymic nitrosative up-regulation. Males have shown increased phenolic content in blood after treatment. L. grisebachii and I. paraguariensis treatment exhibited incomplete antioxidation and oxidative induction in the studied tissues. Different results according to sex were found in redox response to phenolics and their kinetics, with males showing antioxidant effects, whereas females showed oxidative susceptibility. A. quebracho-blanco exhibited protection of murine tissues against oxidation in both sexes and modulation of their trophism, supporting its therapeutic uses in inflammatory diseases. Also, gender had significant influence in phenolic biodistribution and redox response.

Twenty-three indole alkaloids were isolated from Aspidosperma desmanthum and A. spruceanum. Alkaloids 1-4 were isolated from the leaves, 5-8 from the stem bark and 9-15 from the root bark of A. desmanthum. Alkaloids 5, 11, 16, 17 and 19 were isolated from the stem bark, 18 and 20-22 from the root bark and 23 from the flowers of A. spruceanum. Compounds 4, 14, and 15 have not been previously reported as natural products while 16 and 20 have been isolated for the first time from the genus Aspidosperma. Their structures were determined by spectroscopic techniques including 1D and 2D NMR experiments (COSY, NOESY, HSQC, HMBC). The antiparasitic activity of these compounds was tested against Trypanosoma cruzi and Leishmania infantum and their non-specific cytotoxicity on mammalian cells. The most active compounds were 10, 12, 13, and 14 from A. desmanthum, and 19, 21 and 22 from A. spruceanum. Aspidolimine (10) aspidocarpine (12) and tubotaiwine (21) showed selective activity against L. infantum.

The total synthesis of (-)-goniomitine has been accomplished in 11 steps starting from commercially available diethyl l-malate. The synthesis features a chiral pool approach to prepare the chiral C-9 unit containing a quaternary carbon center, an Ir-catalyzed C-H borylation to synthesize the 2-indoleboronic acid pinacol ester, and a Suzuki reaction to couple together the two key intermediates. Notably, the high degree of convergence of this strategy makes it particularly amenable to the total synthesis of other aspidosperma family natural products.

The first total synthesis of indole alkaloid (±)-subincanadine E has been accomplished. Ni(COD)2-mediated intramolecular Michael addition and zinc-mediated fragmentation reaction served as two key transformations.