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The molecular network-guided exploration of the alkaloid extract of Callichilia inaequalis stems revealed a cluster attributed tentatively to dimeric monoterpene indole alkaloids of the rare criophylline subtype, initiating the dual study reported herein. A patrimonial-themed portion of this work was aimed at performing a spectroscopic reassessment of criophylline (1), a monoterpene bisindole alkaloid for which the nature of the inter-monomeric connectivity and configurational assignments have remained dubious. A targeted isolation of the entity annotated as criophylline (1) was undertaken to strengthen the available analytical evidence. An extensive set of spectroscopic data was acquired from the authentic sample of criophylline (1a) isolated earlier by Cavé and Bruneton. These spectroscopic studies proved the samples to be identical, and the complete structure of criophylline could be assigned, half a century after it was first isolated. The absolute configuration of andrangine (2) was also ascertained based on a TDDFT-ECD approach from the authentic sample. The forward-looking aspect of this investigation resulted in the characterization of two new criophylline derivatives from C. inaequalis stems, namely, 14'-hydroxycriophylline (3) and 14'-O-sulfocriophylline (4). Their structures, including absolute configurations, were elucidated by analysis of NMR and MS spectroscopic data and by ECD analysis. Notably, 14'-O-sulfocriophylline (4) is the first sulfated monoterpene indole alkaloid to have been reported. The antiplasmodial activity against the chloroquine-resistant strain of Plasmodium falciparum FcB1 was determined for criophylline and its two new analogues.
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Alcaloides , Antineoplásicos , Tabernaemontana , Alcaloides/química , Cloroquina , Alcaloides Indólicos/química , Monoterpenos , Estructura MolecularRESUMEN
Malaria, a disease known for thousands of years and caused by parasites of the Plasmodium genus, continues to cause many deaths throughout the world today, particularly due to the emergence of parasite resistance to the current therapeutic arsenal. Plants of the Strychnos genus, remarkable due to their multiple traditional uses as well as their alkaloid content, are promising candidates to develop new antimalarial treatments. Indeed, previous research on this plant group has shown promising (≤ 5 µg/ml) or good (between 5 and 15 µg/ml) antiplasmodial activities. Using the chloroquine-sensitive strain of Plasmodium falciparum (3D7), and artemisinin as positive control, a screening of antiplasmodial activities from 43 crude methanolic extracts from 28 species of the Strychnos genus was carried out in three independent assays. A total of 12 extracts had good (6 extracts) or promising (6 extracts) antiplasmodial activities. These results allowed both to confirm known activities but also to detect new ones. These extracts were then analyzed by HPLC-ESI(+)-Q/TOF, and the processed MS/MS data allowed to generate a molecular network in which the antiplasmodial activities were implemented as metadata. The exploration of the molecular network revealed the presence of alkaloids still unknown, and potentially active against malaria, in particular alkaloids close to usambarensine and its derivatives. This study shows that the emergence of molecular networking offers new leads for identifications of alkaloids from the Strychnos genus. The presence of unknown alkaloids potentially active against malaria confirms all the interest to continue in studying the Strychnos genus. Bioassay- and mass-guided fractionations as well as various dereplication tools would allow to identify and characterize these interesting alkaloids further.
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This data descriptor reports on the upload to a public repository (GNPS) of the IQAMDB, IsoQuinoline and Annonaceous Metabolites Data Base, comprising 320 tandem mass spectra. This project originated from our in-house collection of isoquinolines. The diversity of compounds included in this database was further extended through the contribution of two additional laboratories involved in isoquinoline alkaloids research: University of Angers and University of Manaus. The generated MS/MS data were processed and annotated on an individual basis to promote their straightforward reuse by natural product chemists interested in either the description of new isoquinoline alkaloids or the dereplication of isoquinoline-containing samples. The interest of the current repertoire for dereplication purposes has been validated based on the molecular networking of the well-investigated plant model Annona montana against the IQAMDB-implemented GNPS.
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INTRODUCTION: Plants of the Strychnos genus, which include about 200 species, are used for multiple traditional purposes as hunting poison, for example, and have shown interesting pharmacological properties, especially curarizing and tetanizing, but also against malaria. Many monoterpene indole alkaloids have already been isolated and identified. Among them, there is strychnine, a famous alkaloid that can cause death by asphyxiation. OBJECTIVE: Investigate alkaloidic molecular diversity from Strychnos genus using molecular networking technique and study the Strychnos genus from a chemotaxonomic point of view. MATERIAL AND METHODS: Twenty-eight different species and different plant parts were ground into powder using a grinder. The methanolic extracts were carried out using a pressurized solvent extraction and the alkaloid extract was performed manually with a separating funnel. The extracts were analyzed by HPLC-ESI(+)-Q/TOF. The data were processed using MZmine 2 software and the molecular network was generated on the GNPS platform. The study of the generated molecular network allowed the detection of various alkaloids. Among these is the famous strychnine which has been detected in 7 new Strychnos species not yet described as strychnine producers. This identification was investigated using orthogonal approaches, namely TLC, NMR, HPLC-UV and UHPLC-ESI(+)-Q/TOF analyses. The LOD by HPLC-UV of strychnine was also determined. RESULTS: Further analyses allowed to confirm the presence of strychnine in S. densiflora trunk barks but also to show the presence of strychnine with high probability in the trunk barks of S. camptoneura, S. congolana, S. boonei, and S. tchibangensis, and in the leaves of S. usambarensis. About the trunk barks of S. tricalyisoides, the probability of a strychnine content remains low. CONCLUSION: This work exemplified the efficiency of molecular networking in identifying known metabolites (major and minor alkaloids) involved in the chemotaxonomic study of plants from Strychnos genus.
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Alcaloides , Strychnos , Alcaloides/química , Alcaloides Indólicos , Hojas de la Planta , Estricnina/química , Estricnina/farmacología , Strychnos/químicaRESUMEN
In less than 10 years, molecular networking (MN) strategy has revolutionized the art of Natural Products (NP) isolation to enter a rational workflow greatly increasing the probabilities of isolating new chemical entities. To pinpoint and streamline the isolation of new Monoterpene Indole Alkaloids (MIAs) in producing plants, we rendered publicly available the MIA database (MIADB), comprising MS2 data for ca. 200 structurally diverse MIA, by uploading it to the Global Natural Products Social Molecular Networking (GNPS) platform. Here, we describe the key experimental aspects underlying data collection, data curation, and their subsequent upload to the GNPS libraries as a database. Practical tips are also provided at the end of this chapter to help optimizing the efficiency of the dereplication of MIA-containing plants against the MIADB-implemented GNPS library.
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Productos Biológicos , Espectrometría de Masas en Tándem , Productos Biológicos/química , Curaduría de Datos , Alcaloides Indólicos/química , Monoterpenos , PlantasRESUMEN
The structure elucidation of theionbrunonine C, a thioether-bridged dimeric monoterpene indole alkaloid (MIA), and more generally, one of the very few sulfur-containing MIA, is reported after its isolation from Mostuea brunonis (Gelsemiaceae). This unstable structure had already been targeted for isolation in our former, molecular network-guided, investigation of this plant, but this compound had degraded before sufficient spectroscopic data could have been acquired for a complete structure assignment. With this constraint in mind, the rapid acquisition of nuclear magnetic resonance (NMR) data enabled retrieving sufficient spectroscopic information for full structure elucidation, although from a partial set of spectroscopic information (1 H and 13 C NMR; COSY, HSQC, and HMBC). In conjunction with biosynthetic considerations, the cursory examination of 13 C NMR data unambiguously defined the complete stereostructure of 1, as further supported by density functional theory (DFT)-NMR calculations and subsequent DP4 probability score.
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Alcaloides Indólicos , Óxidos , Estructura Molecular , Teoría Funcional de la Densidad , Espectroscopía de Resonancia Magnética , Alcaloides Indólicos/químicaRESUMEN
Annonaceous acetogenins are natural products held responsible for atypical Parkinsonism due to chronic consumption in traditional medicine or as food, leading to the development of analytical strategies for their complete chemical characterization in complex mixtures. Characterization by tandem mass spectrometry (MS/MS) of acetogenins using collision-induced dissociation from lithium adducts provides additional structural information compared to protonated or sodiated species such as ketone location on the acetogenin backbone. However, very low intensity diagnostic ions together with the lack of extensive structural information regarding position of OH and THF substituents limit this approach. Copper adducts led to diagnostic fragment ions that allow us to identify the position of oxygen rings and hydroxyl substituents. Fragmentation rules were established on the basis of acetogenin standards allowing the identification of 45 over the 77 analogues observed in an extract of Annona muricata by LC-MS/MS using postcolumn infusion of copper sulfate (CuSO4) solution. Molecular networks that were generated thanks to specific fragmentations obtained with copper led to the distinction of THF ring position or to the identification of hydroxylated lactone, for instance.
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Acetogeninas , Annona , Acetogeninas/análisis , Acetogeninas/química , Annona/química , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Cobre , Litio , Espectrometría de Masas en TándemRESUMEN
Melonine is a basic monoterpene indole alkaloid (MIA) skeleton from Melodinus philliraeoides that was reported in 1983. The scarcity of its spectroscopic data questioned the validity of its structure. This prompted us to reisolate this molecule and to revise its structure into an unprecedented MIA scaffold. DFT-validated biosynthetic paths to both this new core and the originally reported form are proposed. The pathway to the original structure of melonine seems to be thermodynamically feasible, and that compound may exist as a natural product.
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Apocynaceae/química , Alcaloides Indólicos/química , Monoterpenos/química , Productos Biológicos , Alcaloides Indólicos/síntesis química , Estructura Molecular , Monoterpenos/síntesis químicaRESUMEN
Hemitheion (1), a new sulfur-containing vobasane-type indole alkaloid, was isolated, together with three known compounds, vobasine (2), gelsedine (3), and gelsemicine (4), from the alkaloid extract of the stems of Mostuea brunonis Didr. (Gelsemiaceae). Compound 1 could be straightforwardly isolated. Its structure was elucidated by a combination of spectroscopic methods. Besides corresponding to a formerly postulated biosynthetic intermediate toward theionbrunonines, hemitheion (1) stands among the few monomeric vobasanes lacking an oxygen at C-3. Hemitheion (1) showed moderate antiplasmodial activity in the micromolar range against the strain FcB1 of Plasmodium falciparum and no cytotoxic activity against the MRC-5 cell line at 20 µM.
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Antimaláricos/farmacología , Alcaloides Indólicos/farmacología , Loganiaceae/química , Antimaláricos/aislamiento & purificación , Línea Celular , Gabón , Humanos , Alcaloides Indólicos/aislamiento & purificación , Estructura Molecular , Oxindoles , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Tallos de la Planta/química , Plasmodium falciparumRESUMEN
During our research to contribute to the elucidation of the chemical composition of the root bark of E. suaveolens, six non-nitrogenous cassane diterpenoids (1-6) were isolated and identified. Of these secondary metabolites, three have never been previously described: Cassan-13,15-dien-3-oxo-17-oic acid (2), Cassan-15-en-[7,17]-γ-lactone (3) and 6α-hydroxy-cassamic acid (5). The other are known but, never isolated from the root barks of E. suaveolens (Fabaceae): Cassan-13,15-dien-17-oic acid (1), 6α-hydroxy-cassamic acid methyl esther (4) and cassamic acid (6). Their structures were established according to the spectroscopic data (NMR 1D and 2D, HR-ESI-MS and IR), in comparison with those of literature. The originality of this study lies in the fact that three new natural molecules were isolated and identified. In addition, all the isolated compounds (1-6) were reported for the first time from the root barks of E. suaveolens.
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Diterpenos/aislamiento & purificación , Fabaceae/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Diterpenos/química , Corteza de la Planta/química , Raíces de Plantas/química , Espectroscopía de Protones por Resonancia MagnéticaRESUMEN
Bioassay guided fractionation of the stem barks of Isolona cooperi led to the isolation of a new lactone, apoprunellelactone (APL, 1), and two known compounds, 5-[1-hydroxyhexyl]-2H-furan-2-one (2) and oleic acid (3). Their structures were elucidated by spectral analysis including MS, UV, IR, 1D and 2D-NMR spectroscopy. Evaluated for its antiprotozoal activities, APL (1) was found to be the most active on Leishmania donovani and L. major promastigotes with EC50 values of 16.3 and 8.2 µM, respectively. Against Trypanosoma brucei brucei trypomastigote forms, the activity of APL was moderated (MEC = 38.0 µM). Its hemisynthetic ester acetic derivative (1c) was 2-42 times more active than that of the APL and reference drugs, justifying further in vivo evaluation of the two compounds (1 and 1c) on Leishmania sp and Trypanosoma brucei brucei/mice models.
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Annonaceae , Antiprotozoarios , Leishmania donovani , Trypanosoma brucei brucei , Animales , Antiprotozoarios/farmacología , Lactonas , RatonesRESUMEN
Four undescribed alkaloids have been isolated from the bulbs of the previously unstudied Crinum scillifolium. These compounds were targeted following a state-of-the-art molecular networking strategy comprising a dereplication against in silico databases and re-ranking of the candidate structures based on taxonomically informed scoring. The unreported structures span across a variety of Amaryllidaceae alkaloids appendages. Their structures were unambiguously elucidated by thorough interpretation of their HRESIMS and 1D and 2D NMR data, and comparison to literature data. DFT-NMR calculations were performed to support the determined relative configurations of scillitazettine and scilli-N-desmethylpretazettine and their absolute configurations were mitigated by comparison between experimental and theoretically calculated ECD spectra. The lack of a methyl group on the nitrogen atom in the structure of scilli-N-desmethylpretazettine series is highly unusual in the pretazettine/tazettine series but the most original structural feature in it lies in its 11α disposed hydrogen, which is new to pretazettines. The antiplasmodial as well as the cytotoxic activities against the human colon cancer cell line HCT116 were evaluated, revealing mild to null activities.
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Alcaloides , Alcaloides de Amaryllidaceae , Crinum , Alcaloides/farmacología , Alcaloides de Amaryllidaceae/farmacología , Humanos , Estructura Molecular , Extractos Vegetales , Raíces de PlantasRESUMEN
Five new cassane-type diterpenoid heterosides, i. e. two cassane-type amides (1-2), two erythrophlamine-type amine esters (3-4) and a nonnitrogenous erythrophlamine analogue (5) were isolated from the root barks (1-2) and the seeds (3-5) of Erythrophleum suaveolens. Their structures were unambiguously established by interpretation of their HRESIMS, 1D and 2D NMR data, and chemical degradation for sugar determination. Compounds 3-5 were evaluated for their cytotoxicity against a panel of three cell lines, revealing modest to strong activities.
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Antineoplásicos Fitogénicos/farmacología , Diterpenos/farmacología , Fabaceae/química , Corteza de la Planta/química , Semillas/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Côte d'Ivoire , Diterpenos/aislamiento & purificación , Humanos , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacologíaRESUMEN
Inaequalisines A and B (1 and 2), the first examples of hybrid alkylated phenylpropane monoterpene indole alkaloids, were isolated from the roots of Callichilia inaequalis, guided by the combined use of molecular networking and substructure annotation. Their structures, including absolute configuration, were elucidated by spectroscopic methods and ECD calculations. A possible biosynthetic pathway for 1 and 2 was postulated.
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Epicatechocorynantheines A and B, and epicatechocorynantheidine were isolated from the stem bark of Corynanthe pachyceras. These molecules were pinpointed, and their isolation streamlined, by a molecular networking strategy. The structural elucidation was unambiguously accomplished from HRMS and 1D/2D NMR data. These compounds represent the first examples of corynanthean-type alkaloids tethered with a flavonoid. Epicatechocorynantheidine notably instigated two connections between the monoterpene indole alkaloid and the flavonoid, yielding an unprecedented octacyclic appendage. These flavoalkaloids exerted moderate antiplasmodial activities.
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Antihelmínticos/farmacología , Catequina/química , Flavonoides/química , Alcaloides Indólicos/química , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Monoterpenos/química , Pausinystalia/química , Corteza de la Planta/química , Tallos de la Planta/químicaRESUMEN
Traditional natural products discovery workflows implying a combination of different targeting strategies, including structure- and/or bioactivity-based approaches, afford no information about new compound structures until late in the discovery pipeline. By integrating a MS/MS prediction module and a collaborative library of (bio)chemical transformations, we have developed a new platform, coined MetWork, that is capable of anticipating the structural identity of metabolites starting from any identified compound. In our quest to discover new monoterpene indole alkaloids, we demonstrate the utility of the MetWork platform by anticipating the structures of five previously undescribed sarpagine-like N-oxide alkaloids that have been targeted and isolated from the leaves of Alstonia balansae using a molecular networking-based dereplication strategy fueled by computer-generated annotations. This study constitutes the first example of nonpeptidic molecular networking-based natural product discovery workflow, in which the targeted structures were initially generated, and therefore anticipated by a computer prior to their isolation.
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Alcaloides/química , Productos Biológicos/química , Diseño Asistido por Computadora , Alcaloides/aislamiento & purificación , Alstonia/química , Productos Biológicos/aislamiento & purificación , Conformación Molecular , Hojas de la Planta/química , Espectrometría de Masas en TándemRESUMEN
The data are related to the research article entitled ''New cassane diterpenoids from the root bark of Erythrophleum suaveolens'' (Jacques et al., 2019). The article provides method of purification and data to determine structure of two novel cassane diterpenoid amines: 3ß-hydroxy-3-methylbutanoyloxy-6α-hydroxy-nor-cassamine (1) and 3ß-hydroxy-3-methylbutanoyloxy-erythrosuamine (2). This data in brief provides IR, NMR and Q-TOF-MS spectra, along with fragmentation pathways that allowed to the identification of both new compounds.
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Covering: up to 2019Landmark advances in bioinformatics tools have recently enhanced the field of natural products research, putting today's natural product chemists in the enviable position of being able to perform the efficient targeting/discovery of previously undescribed molecules by expediting the prioritization of the isolation workflow. Among these advances, MS/MS molecular networking has appeared as a promising approach to dereplicate complex natural product mixtures, leading to a real revolution in the "art of natural product isolation" by accelerating the pace of research of this field. This review illustrates through selected cornerstone studies the new thinking in natural product isolation by drawing a parallel between the different underlying philosophies behind the use of molecular networking in targeting natural products.
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Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Espectrometría de Masas , Redes y Vías MetabólicasRESUMEN
This Data Descriptor announces the submission to public repositories of the monoterpene indole alkaloid database (MIADB), a cumulative collection of 172 tandem mass spectrometry (MS/MS) spectra from multiple research projects conducted in eight natural product chemistry laboratories since the 1960s. All data have been annotated and organized to promote reuse by the community. Being a unique collection of these complex natural products, these data can be used to guide the dereplication and targeting of new related monoterpene indole alkaloids within complex mixtures when applying computer-based approaches, such as molecular networking. Each spectrum has its own accession number from CCMSLIB00004679916 to CCMSLIB00004680087 on the GNPS. The MIADB is available for download from MetaboLights under the identifier: MTBLS142 ( https://www.ebi.ac.uk/metabolights/MTBLS142 ).
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Theionbrunonines A and B (1 and 2), the first examples of monoterpene bisindole alkaloids linked by a thioether bridge, were isolated from the stems of Mostuea brunonis, guided by a molecular networking-based dereplication strategy. Their structures were elucidated by a combination of spectroscopic data and ECD calculations. A plausible biosynthetic pathway for 1 and 2 was postulated. Theionbrunonines A and B (1 and 2) showed moderate antiplasmodial activities in the micromolar range against the strain FcB1 of Plasmodium falciparum and no cytotoxic activity against the MRC-5 cell line at 20 µM.