Advances and Strategies towards Synthesis of Aspidosperma Indole Alkaloids Goniomitine.

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.

Vincazalidine A, a unique bisindole alkaloid from Catharanthus roseus.

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.

A Homo-Mannich Reaction Strategy Enables Collective Access to Ibophyllidine, Aspidosperma, Kopsia, and Melodinus Alkaloids.

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.

Diverse aspidosperma-type alkaloids from the leaves of Tabernaemontana bovina with anti-hepatoma activity.

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.

Antihypertensive Activity of the Alkaloid Aspidocarpine in Normotensive Wistar Rats.

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.

Activity of alkaloids from Aspidosperma nitidum against Leishmania (Leishmania) amazonensis.

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 1H 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.

Semi-syntheses and interrogation of indole-substituted Aspidosperma terpenoid alkaloids.

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.

Evaluation of acute and subacute toxicity of ethanolic extract and fraction of alkaloids from bark of Aspidosperma nitidum in mice.

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.

Quorum sensing inhibitory effect of bergamot oil and aspidosperma extract against Chromobacterium violaceum and Pseudomonas aeruginosa.

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.

Structural basis of cycloaddition in biosynthesis of iboga and aspidosperma alkaloids.

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.

Protecting-Group-Free Formal Synthesis of Aspidospermidine: Ring-Opening Cyclization of Spirocyclopropane with Amine Followed by Regioselective Alkylations.

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.

Asymmetric Total Synthesis of (+)-Winchinine B.

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.

Isolation and Antimacrofouling Activity of Indole and Furoquinoline Alkaloids from 'Guatambú' Trees (Aspidosperma australe and Balfourodendron riedelianum).

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.

Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization.

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 IC50 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 ß-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.

Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization.

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.

Conolodinines A-D, Aspidosperma- Aspidosperma Bisindole Alkaloids with Antiproliferative Activity from Tabernaemontana corymbosa.

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 IC50 values for the active compounds in the 0.01-5 µM range.

Aspidosperma species: A review of their chemistry and biological activities.

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.

A unified synthesis of topologically diverse Aspidosperma alkaloids through divergent iminium-trapping.

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.

Aspidosperma pyrifolium, a medicinal plant from the Brazilian caatinga, displays a high antiplasmodial activity and low cytotoxicity.

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 MDL50 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.

Bisleuconothines B-D, Modified Eburnane-Aspidosperma Bisindole Alkaloids from Leuconotis griffithii.

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 (IC50 > 10 µM) when tested against A549 human lung adenocarcinoma cells.