Search

The structure and complete NMR assignments of aspidoreticulofractine, an aspidofractinine N-oxide, are reported. Its structure was elucidated based on a combination of spectroscopic techniques including 1D and 2D NMR, high-resolution mass spectrometry, and electronic circular dichroism.

A new vobasine–tryptamine-based monoterpene indole alkaloid pseudodimer was isolated from the stem bark of Voacanga africana. As a minor constituent occurring in a thoroughly investigated plant, this molecule was targeted based on a molecular networking strategy and a rational MS2-guided phytochemical investigation led to its isolation. Its structure was formally established based on HRMS, 1D/2D NMR data, and the application of the tool Small Molecule Accurate Recognition Technology (SMART 2.0). Its absolute configuration was assigned by the exciton chirality method and TD-DFT ECD calculations. Besides featuring an unprecedented intermonomeric linkage in the small group of vobasine/tryptamine hybrids, pyrrovobasine also represents the first pyrraline-containing representative in the whole monoterpene indole alkaloids group. Biosynthetic hypotheses possibly underpinning these structural oddities are proposed here.

A key bottleneck in the study of biosynthetic pathways for complex natural products is identifying the appropriate mechanisms and conditions to assemble intricated skeletons, especially when no genomic or proteomic data are available. In this regard, a chemoinformatic exploration of highly textured knowledge generated by chemical synthesis experiments can address this issue and become part of a general method for the analysis of information-rich high-throughput experiments of multicomponent reactions. Starting from a bio-inspired experimental design, we have applied a combined screening and selection approach, leveraging reaction conditions and synthetic probe-informed molecular networking workflow. This procedure quickly pinpointed relevant bio-inspired reaction conditions that may follow Baldwin and Whitehead renowned hypothesis for the biosynthesis of Manzamine-type alkaloids. A model for keramaphidin B, collapsing a multi–step synthesis into a one-pot reaction, was devised for this purpose providing important information in terms of biosynthesis.

We herein report on the first chemical assessment of Erythrococca anomala (Juss. ex Poir.) Prain (Euphorbiaceae), a genus that was – to the best of our knowledge – not studied yet from a phytochemical perspective. A molecular networking strategy was implemented to rapidly identify the known specialized metabolites from untargeted MS/MS analyses of E. anomala leaves ethanolic extract. This strategy allowed for the identification of diverse C-glycosyl flavones and a cursory examination of MS/MS spectra could extend the GNPS-provided annotation to pinpoint the structural novelty of further derivatives. The isolation of the sought-after structures could be streamlined based on MS-guidance and their structures, determined through extensive NMR analyses, displayed structural features in line with MS²-based predictions. Anticipating sharp structural features at an early stage of the dereplication process through a critical assessment of the tandem mass spectrometric landmarks was essential to embark on the isolation of the newly reported structures owing to the elevated number of flavonoid glycosides isomers thereof formerly known, which would have deterred us from isolating them without the support of additional tandem mass spectrometric information. The isolation of the main components of the ethanolic extract completed the currently provided chemical report on E. anomala, also resulting in the description of a new phenylethanoid derivative (3) and of a new orcinol-based dimer (4). Anomaloflavone (1) exhibit significant activities with minimal inhibitory concentration values of 25 µg/mL against Staphylococcus aureus and Mycobacterium smegmatis while failing to exert an antibacterial activity against Pseudomonas aeruginosa, while being devoid of cytotoxicity against SiHa cells.

Lyaline (1) is a monoterpene indole alkaloid that was isolated in 1974 from Pauridiantha lyallii (Rubiaceae) in our laboratory and has not been reported elsewhere since then. Its structure was proposed on the basis of a very limited set of spectroscopic data (viz., 1H NMR and EIMS) as a structurally bizarre harman-1,4-dihydropyridine derivative. A total synthesis of this proposed structure 30 years later proved this product to be highly unstable, and inconsistencies with the original limited spectroscopic data indicated that the structure proposed for lyaline was incorrect. Having in our laboratory the initial and unique lyaline sample, we decided to reinvestigate it using modern spectroscopic techniques, 47 years after its isolation. Our new spectroscopic data confirmed that the initially assigned harman-1,4-dihydropyridine structure was incorrect, instead establishing lyaline as the first naturally occurring nacycline analogue. This structure revision substantiates a type of chemical reactivity of strictosidine first reported in 1975.

The structure and complete nuclear magnetic resonance (NMR) assignments of orbifomitellic acid, a novel lanostane triterpene isolated from the fruiting bodies of a Gabonese Ganoderma orbiforme (Polyporaceae), are reported. Within the vast catalogue of lanostanes documented from Ganoderma spp., orbifomitellic acid is the first disclosing a -COOH group at C-4.

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.

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 (

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.

International audience; Voatriafricanines A and B (1 and 2), the first examples of vobasine-aspidosperma-aspidosperma monoterpene trisindole alkaloids, were isolated from the stem barks of Voacanga africana, guided by a molecular networking strategy. Their structures, including absolute configurations, were elucidated by spectroscopic methods and ECD calculations. Compounds 1 and 2 possess intramolecular hydrogen bonding, sufficiently robust to transfer homonuclear and heteronuclear magnetizations. Compound 1 exhibited potent antimycobacterial activity with no discernible cytotoxic activity.

Voatriafricanines A and B (

International audience; We report the enantioselective total syntheses of mavacurans alkaloids, (+)-taberdivarine H, (+)-16-hydoxymethylpleiocarpamine, (+)-16-epi-pleiocarpamine, and their postulated biosynthetic precursor 16-formyl-pleiocarpamine. This family of monoterpene indole alkaloids is a target of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline. Inspired by the biosynthetic hypothesis, we explored an oxidative coupling approach from the geissoschizine framework to form the N1-C16 bond. Quaternization of the aliphatic nitrogen was key to achieve the oxidative coupling induced by KHMDS/I2 since it hides the nucleophilicity of the aliphatic nitrogen and locks the required cis conformation. Scheme 3. Synthesis of 16-deformyl-geissoschizine (22), geissoschizine (1) and geissoschizine malonate 23 according to our previous work. With a straightforward access to the geissoschizine framework, we were in position to evaluate our hypothesis of oxidative cyclization after quaternization of the aliphatic nitrogen N4. As

Among the outstanding chemical diversity found in marine sponges, cyclic guanidine alkaloids, present in species of the family Crambeidae, are particularly attractive, not only because of their unique chemical features, but also due to a broad range of biological activities. Despite a growing interest in these natural products as therapeutic agents, their metabolic pathway has not been experimentally investigated. Ex situ feeding experiments using radiolabeled precursors performed on the Mediterranean sponge Crambe crambe suggest arginine and fatty acids as precursors in the metabolic pathway of crambescins. A subsequent bio-inspired approach supported the change of paradigm in the metabolic pathway of cyclic guanidine alkaloids. A large part of the chemical diversity of this family would therefore originate from a tethered Biginelli-like reaction between C-2/C-3 activated fatty acids and a central guanidinylated pyrrolinium.

International audience; 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.

International audience; Five new monoterpene indole alkaloids (1-5), including four serpentinine-related bisindoles and one alstonine derivative monomer, have been isolated from the aerial parts of Picralima nitida. Their structures were elucidated by analysis of their HRMS and NMR spectroscopic data, and their absolute configurations were deduced from the comparison of experimental and simulated ECD spectra. In addition, two known compounds (6 and 7), previously undescribed from P. nitida, have also been purified. The compound isolation workflow was guided by a molecular networking-based dereplication strategy. Twenty-three compounds were dereplicated from the EtOH extract of P. nitida and fractions network and were assigned various levels of identification confidence. The antiparasitic activities against Plasmodium falciparum as well as the cytotoxic activity against the MRC-5 cell line were determined for compounds 1-7.

Context. Camellimidazoles A–C were recently reported as new natural substances arising from what was described as new caffeine degradation pathway in Keemun black tea. - Discoveries. Under alkaline hydrolysis conditions followed by spontaneous cascade reactions with formaldehyde or dichloromethane (as the key methylene group providers), we were able to achieve the synthesis of camellimidazoles B and C. A MetWork-based pipeline was also implemented highlighting a wealth of structurally diverse compounds formed in the course of the reaction and streamlining the isolation of the newly described camellimidazoles D-F, subsequently confirmed as anticipated in silico upon extensive spectroscopic analyses. Besides demonstrating the artefactual origin of camellimidazoles, the current investigation emphasizes the fitness of MetWork-tagging to illuminate the chemical diversity associated with seemingly simple reactive conditions.- Methods. Organic synthesis, phytochemical analysis, in silico anticipation, molecular networking dereplication

International audience; Three new xanthone dimers, eumitrins C - E (1-3), along with a new depsidone, 3'-O-demethylcryptostictinolide (4) were isolated from the acetone extract of the whole thallus of the lichen Usnea baileyi collected in Vietnam. Their structures were unambiguously established by spectroscopic analyses (HRESIMS, 1D and 2D NMR), as well as comparison to literature data. The absolute configurations of 1-3 were elucidated through electronic circular dichroism (ECD) analyses. The absolute configuration of 2 was validated by comparison between experimental and TDDFT-calculated ECD spectra while that of 3 was based on DFT-NMR calculations and subsequent DP4 probability score. The antiparasitic activities against Plasmodium falciparum as well as the cytotoxic activity against seven cell lines were determined for the new compounds 1-3, and led from null to mild bioactivities.

Five new monoterpene indole alkaloids (

We propose a biodereplication method using mass spectrometry and combining the classical dereplication approach with the predominant mechanism of action of antimalarial drugs. The method encompasses a biomimetic heme binding assay (heme adducts detection by MS), molecular networking for quick data mining, CPC for extract fractionation and compounds isolation and in silico modeling of heme adducts by molecular docking.

Micro- and nano-platelets are a group of particles with typical flat surfaces and hexagonal shape. They are obtained by hierarchical self-assembly in water of α-cyclodextrin and polysaccharides hydrophobically-modified with alkyl chains. It is expected that the formation of well structured and cohesive platelets is driven by the interaction between alkyl chains grafted on polysaccharides and α-cyclodextrin. The objective of this investigation is to tune platelet formation by modifying these two parameters, independently on polysaccharide composition. A systematic study was conducted by varying polysaccharide type (dextran, pullulan, amylopectin), degree of substitution (DS:0.1–5.6%) and α-cyclodextrin concentration (0–10 wt%) for a fixed concentration of polysaccharide esterified with palmitoyl groups (1 wt%). Characterizations include ATR-FTIR, elemental analysis, solid state 13C NMR and transmission electron microscopy. Abundant and well-organized hexagonal platelets were obtained with high DS (4.2–5.6%) and a concentration of α-cyclodextrin higher than 2.5 wt%. Isothermal titration calorimetry revealed a sequential binding with a stoichiometry of 2 α-cyclodextrin molecules for 1 palmitoyl group grafted on dextran. This is the first report showing the possibility to control platelet formation by modifying DS and α-cyclodextrin concentration, independently on polysaccharide composition.

Bipleiophylline is a highly complex monoterpene indole alkaloid composed of two pleiocarpamine units anchored on an aromatic spacer platform. The synthesis of bipleiophylline is considered as a mountain to climb by the organic chemistry community. Here, a unified oxidative coupling protocol between indole derivatives and 2,3-dihydroxybenzoic acid, mediated by silver oxide, has been developed to produce the core of bipleiophylline. This method also allows the independent preparation of benzofuro[2,3-b]indolenine and isochromano[3,4-b]indolenine scaffolds, depending only on the nature of the aromatic platform used. The procedure has been applied to simple indole derivatives and to more challenging monoterpene indole alkaloids, thereby furnishing natural-product-like structures. The use of scarce pleiocarpamine as the starting indole allows the first syntheses of bipleiophylline and of its biosynthetic precursor, voacalgine A. The structure of the latter has been reassigned in the course of our investigations by 2D NMR and displays an isochromano[3,4-b]indolenine motif instead of a benzofuro[2,3-b]indolenine.

Twenty-nine jatrophane esters (1-10, 12-30) and one lathyrane (11) diterpenoid ester isolated from Euphorbia species were evaluated for their capacity to inhibit drug-efflux activities of the primary ABC transporter CaCdr1p and the secondary MFS transporter CaMdr1p of Candida albicans, in yeast strains overexpressing the corresponding transporter. These diterpenoid esters were obtained from Euphorbia semiperfoliata (1-10), E. insularis (11), and E. dendroides (12-30) and included five new compounds, euphodendroidins P-T (26-30). The jatrophane esters 12 and 23 were found to inhibit the efflux of Nile Red (NR) mediated by the two multidrug transporters, at 85-64% for CaCdr1p and 79-65% for CaMdr1p. In contrast, compound 21 was selective for CaCdr1p and induced a strong inhibition (92%), whereas compound 8 was selective for CaMdr1p, with a 74% inhibition. It was demonstrated further that potency and selectivity are sensitive to the substitution pattern on the jatrophane skeleton. However, these compounds were not transported and showed no synergism with fluconazole cytotoxicity.

International audience; Production and use of the insecticide chlordecone has caused long-term environmental pollution in the James River area and the French West Indies (FWI) that has resulted in acute human-health problems and a social crisis. High levels of chlordecone in FWI soils, even after its ban decades ago, and the absence of detection of transformation products (TPs), have suggested that chlordecone is virtually nonbiodegradable in the environment. Here, we investigated laboratory biodegradation, consisting of bacterial liquid cultures and microcosms inoculated with FWI soils, using a dual nontargeted GC-MS and LC-HRMS approach. In addition to previously reported, partly characterized hydrochlordecones and polychloroindenes (families A and B), we discovered 14 new chlordecone TPs, assigned to four families (B, C, D, and E). Organic synthesis and NMR analyses allowed us to achieve the complete structural elucidation of 19 TPs. Members of TP families A, B, C, and E were detected in soil, sediment, and water samples from Martinique and include 17 TPs not initially found in commercial chlordecone formulations. 2,4,5,6,7-Pentachloroindene was the most prominent TP, with levels similar to those of chlordecone. Overall, our results clearly show that chlordecone pollution extends beyond the parent chlordecone molecule and includes a considerable number of previously undetected TPs. Structural diversity of the identified TPs illustrates the complexity of chlordecone degradation in the environment and raises the possibility of extensive worldwide pollution of soil and aquatic ecosystems by chlordecone TPs.

Penicillium ubiquetum MMS330 isolated from the blue mussel Mytilus edulis collected on the Loire estuary in France was here investigated. As very few secondary metabolites have been documented for this species, its metabolome was studied following the OSMAC approach to enhance as many biosynthetic pathways as possible. Interestingly, HPLC-HRMS based hierarchical clustering analysis together with MS/MS molecular networking highlighted the selective overproduction of some structurally related compounds when the culture was performed on seawater CYA (Czapek Yeast extract Agar) medium. Mass-guided purification from large scale cultivation on this medium led to the isolation of nine meroterpenoids including two new analogues, 22-deoxyminiolutelide A (1) and 4-hydroxy-22-deoxyminiolutelide B (2), together with seven known compounds (3–9). The structures of 1 and 2 were elucidated on the basis of HR-ESIMS and NMR spectroscopic data analysis. Furthermore, NMR signals of 22-deoxyminiolutelide B (3) were reassigned.

A methodological study towards the total synthesis of marmycin A/B is described exploiting a commercial anthraquinone molecule as model compound. The challenging synthetic pathway uncovers a copper-catalysed Ullmann cross-coupling to attach the sugar backbone by means of C–N bond formation and, finally, an intramolecular Friedel–Crafts C–C glycosylation to successfully afford the core structure of marmycin A. This methodology has been successfully applied to the genuine anthraquinone moiety leading to the natural product and simpler structural analogues.

Isolation of marine compounds from living invertebrates represents a major challenge for sustainable and environmentally friendly exploitation of marine bio-resources. To develop innovative technology to trap invertebrate compounds in the open sea, the proof of concept of a system combining external continuous circulation of water with XAD-amberlite solid-phase extraction was validated in an aquarium. In this work, we reported the elicitation of guanidine alkaloid production of Crambe crambe in the presence of Anemonia sulcata, both collected from the Mediterranean Sea. Besides the previously reported crambescidin 359 (1), and crambescidin acid (2), three new compounds were isolated; one carboxylated analog of 1 named crambescidin 401 (3), and two analogs of crambescin B, crambescin B 281 (4) and crambescin B 253 (5). Based on these results, a technology named Somartex® for “Self Operating MARine Trapping Extractor” was patented and built to transfer the concept from closed aquarium systems to open marine ecosystems.

International audience; Six new sulfonic acid-containing flavonoids, acidoflavanone (1), acidoauronol (2), 5- O-methylacidoauronol (3), acidoaurone (4), acidoisoflavone (5), and acidoflavonol (6), were isolated from the EtOH extract of the roots of Phyllanthus acidus. Their structures were unambiguously established by interpretation of their HRESIMS and 1D and 2D NMR data, single-crystal X-ray diffraction analysis, and comparison to the literature data. These new structures represent the first examples of sulfonic acid-containing flavanones, auronols, aurones, and isoflavones.

International audience; Three new jatrophane esters (1−3) were isolated from Euphorbia amygdaloides ssp. semiperfoliata, including an unprecedented macrocyclic jatrophane ester bearing a hemiketal substructure, named jatrohemiketal (3). The chemical structures of compounds 1−3 and their relative configurations were determined by spectroscopic analysis. The absolute configuration of compound 3 was determined unambiguously through an original strategy combining NMR spectroscopy and molecular modeling. Conformational search calculations were performed for the four possible diastereomers 3a−3d differing in their C-6 and C-9 stereocenters, and the lowest energy conformer was used as input structure for geometry optimization. The prediction of NMR parameters (1 H and 13 C chemical shifts and 1 H− 1 H coupling constants) by density functional theory (DFT) calculations allowed identifying the most plausible diastereomer. Finally, the stereostructure of 3 was solved by comparison of the structural features obtained by molecular modeling for 3a−3d with NMR-derived data (the values of dihedral angles deduced from the vicinal proton−proton coupling constants (3 J HH) and interproton distances determined by ROESY). The methodology described herein provides an efficient way to solve or confirm structural elucidation of new macrocyclic diterpene esters, in particular when no crystal structure is available. L ower diterpenoids isolated from Euphorbia species represent a unique group of highly structurally diverse compounds endowed with potent biological activity such as antiviral activities 1 and modulation of PKC and P-glycoprotein activities. 2,3 More than 650 diterpenoids based on 20 types of carbon skeletons have been characterized from this genus so far. 3 The planar structures and the relative configurations of these skeletons have been usually solved by interpretation of NMR spectroscopic data 4−11 or obtained by X-ray crystallographic analysis. 12−18 Conformational search and geometry optimization have also been used to support their structural elucidation based on NMR spectroscopy. 19−30 The absolute configurations of these skeletons have been established using X-ray diffraction analysis 6,17,31,32 or electronic circular dichroism (ECD) data analysis 27−29 or deduced from the NMR data of Mosher esters. 6 Moreover, taking into account that all macrocyclic diterpene esters of the lathyrane 5,16,33 and jatrophane types, 16,17,33 and most of their biogenetically related skeletons, 2,3 possess a constant trans-ring junction with a 4α-proton and 15β-oxygenated functionality, the relative configuration of these diterpenoids can be confidently upgraded to the absolute one. 23,30,34 When no crystal structure is available, the three-dimensional structures of these natural products can be established through the interpretation of NOESY or ROESY experiments along with the analysis of vicinal proton−proton coupling constants 3 J HH , observed in their 1 H NMR spectra. 35 However, based on NMR spectroscopic analysis, the determination of the relative configuration of some new diterpene scaffolds can be challenging. For example, the stereostructure of the tetracyclic pepluane isolated by Jakupovic et al. was misassigned. 21 Despite the authors having performed a molecular modeling analysis, the full stereochemistry of the compound could not be determined. The 3D structure of pepluane was established finally via single-crystal X-ray diffraction study. 36 A conforma-tional study showed that pepluane possesses a relatively rare ring D conformation, which probably led to the misinterpretation of the NMR data. 36 The challenging 3D determination of some jatrophane esters may also be exemplified by a study by Hohmann and associates, in which the relative configuration of esulatin C could not be assigned. 34 The high flexibility of the macrocyclic part of this compound was one of the explanations made. Several studies have shown that jatrophane esters can adopt different conformations depending on their esterification pattern. 37−40 The full structural determination of natural products can be strengthened confidently by molecular modeling and density

Clotrimazole (CTZ) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility were obtained from phase solubility diagrams. β-CD (1.5% w/w) and hydroxypropyl-β-CD (40% w/w) offered poor CTZ solubility enhancements (12 and 384 times, respectively). Unexpectedly, the apparent solubility of CTZ was 9980 times increased from 0.4 µg.mL−1 (1.42 μM) without CD to 4.89 mg.mL−1 (14.9 mM) using randomly-methylated β-CD (Me-β-CD) (40% w/w). This is the highest apparent CTZ solubility improvement ever reported in the literature using conventional CDs. Quantitative nuclear magnetic resonance (1H-NMR) coupled with two-dimensional nuclear Overhauser effect (NOESY) experiments and molecular docking calculations showed that the highest interactions with Me-β-CD were reported for CTZ two phenyl groups. A lower interaction was reported for chlorophenyl, while imidazole had the weakest interaction with Me-β-CD. Copyright © 2015 John Wiley & Sons, Ltd.

A supercritical fluid chromatography-based targeted purification procedure using tandem mass spectrometry and molecular networking was developed to analyze, annotate, and isolate secondary metabolites from complex plant extract mixture. This approach was applied for the targeted isolation of new antiviral diterpene esters from Euphorbia semiperfoliata whole plant extract. The analysis of bioactive fractions revealed that unknown diterpene esters, including jatrophane esters and phorbol esters, were present in the samples. The purification procedure using semipreparative supercritical fluid chromatography led to the isolation and identification of two new jatrophane esters (13 and 14) and one known (15) and three new 4-deoxyphorbol esters (16–18). The structure and absolute configuration of compound 16 were confirmed by X-ray crystallography. This compound was found to display antiviral activity against Chikungunya virus (EC50 = 0.45 μM), while compound 15 proved to be a potent and selective inhibitor of H...

International audience; Three new monoterpene indole alkaloids (13) have been isolated from the bark of Geissospermum laeve-, together with the known alkaloids (-)-leuconolam (4), geissolosimine (5), and geissospermine (6). The structures of 1-3 were elucidated by analysis of their HRMS and NMR spectroscopic data. The absolute configuration of geissolaevine (I). was deduced from the comparison of experimental and theoretically calculated ECD spectra. The isolation workflow was guided by a molecular networking-based dereplication strategy using an in-house database of monoterpene indole alkaloids. In addition, five known compounds previously undescribed in the Geissospermum genus were dereplicated from the G. laeve alkaloid extract network and were assigned with various levels of identification confidence. The antiparasitic activities against Plasmodium falciparum and Leishmania donovani as well as the Ortotoxic activity against the MRC-5 cell line were determined for compounds 1-5.

A supercritical fluid chromatography-based targeted purification workflow using tandem mass spectrometry and molecular networking was developed to analyze, annotate and isolate secondary metabolites from complex mixture. This approach was applied for targeted isolation of new antiviral diterpene esters from Euphorbia semiperfoliata whole plant extract. The analysis of bioactive fractions revealed that unknown diterpene esters, including jatrophane esters and phorboids esters, were present in the samples. The purification procedure using semi-preparative-supercritical fluid chromatography led to the isolation and identification of two jatrophane esters (13 and 14) and four 4-deoxyphorbol esters (15-18). Compound 16 was found to display antiviral activity against chikungunya virus (EC50 = 0.45 µM), while compound 15 was found to be a potent and selective inhibitor of HIV-1 replication in a recombinant virus assay (EC50 = 13 nM). This study showed that supercritical fluid chromatography-based workflow and molecular networking can facilitate and accelerate the discovery of bioactive small molecules by targeted molecules of interest, while minimizing the use of toxic solvents.

Pleiokomenines A and B (1 and 2), first examples of dimeric aspidofractinine alkaloids linked by a methylene bridge, were isolated from the stem bark of Pleiocarpa mutica. Their structures were elucidated by a combination of spectroscopic analyses and semisynthetic derivatization of pleiocarpinine (3) and a formaldehyde equivalent mediated by scandium trifluoromethanesulfonate. Pleiokomenines A (1) and B (2) showed moderate antiplasmodial activities in the micromolar range against the FcB1 strain.

WOS:000413167100012; International audience; Guided by a "chemistry first" approach using molecular networking, eight new bright-blue colored natural compounds, namely dactylocyanines A-H (3-10), were isolated from the Polynesian marine sponge Dactylospongia metachromia. Starting from ilimaquinone (1), an hemisynthetic phishing probe (2) was prepared for annotating and matching structurally related natural substances in D. metachromia crude extract network. This strategy allowed characterizing for the first time in Nature the blue zwitterionic quinonoid chromophore. The solvatochromic properties of the latter are reported.

International audience; An efficient process was used to isolate six new jatrophane esters, euphodendroidins J (3), K (5), L (6), M, (8), N (10), and O (11), along with seven known diterpenoid esters, namely, euphodendroidins A (4), B (9), E (1), and F (2), jatrophane ester (7), and 3α-hydroxyterracinolides G and B (12 and 13), and terracinolides J and C (14 and 15) from the latex of Euphorbia dendroides. Their 2D structures and relative configurations were established by extensive NMR spectroscopic analysis. The absolute configurations of compounds 1, 11, and 15 were determined by X-ray diffraction analysis. Euphodendroidin F (2) was obtained in 18% yield from the diterpenoid ester-enriched extract after two consecutive flash chromatography steps, making it an interesting starting material for chemical synthesis. Euphodendroidins K and L (5 and 6) showed an unprecedented NMR spectroscopic behavior, which was investigated by variable-temperature NMR experiments and molecular modeling. The structure–conformation relationships study of compounds 1, 5, and 6, using DFT-NMR calculations, indicated the prominent role of the acylation pattern in governing the conformational behavior of these jatrophane esters. The antiviral activity of compounds 1–15 was evaluated against Chikungunya virus (CHIKV) replication.

Sch-642305 is the major compound produced by the endophytic fungi Phomopsis sp. CMU-LMA . Incubation of Sch-642305 with Aspergillus ochraceus ATCC 1009 resting cells leads to three new derivatives through an oxido-reduction of the six-membered ring of the molecule. Reduction of the double bound leads to compound ( 1 ), which subsequently undergoes carbonyl reduction to ( 2 ) and ring hydroxylation to ( 3 ). According to the previously solved crystal structure of Sch-642305 coupled with 1 H NMR NOE correlation and the crystal structure of compound 1 , the absolute configurations of the new derivatives were established. In contrast to the parent compound Sch-642305, compound ( 1 ) exhibits antimicrobial activity against Gram-negative bacteria. Furthermore, while all derivatives exhibit cytotoxic activity against various cancer cell lines, compound ( 2 ) achieved an IC 50 of 4 nM against human myelogenous leukemia K 562, compared to 20 nM for the parent Sch-642305.

International audience; The study of the n-butanol extract of the New Caledonian sponge Agelas dendromorpha led to the isolation and identification of three new pyrrole-2-aminoimidazole (P-2-AI) alkaloids, named agelastatins E (3) and F (4) and benzosceptrin C (5), together with 10 known metabolites, agelastatin A (1), agelastatin D (2), sceptrin (6), manzacidin A, tauroacidin A, taurodispacamide A, nortopsentin D, thymine, longamide, and 4,5-dibromopyrrole-2-carboxamide. Their structures were assigned by spectroscopic data interpretation. All the compounds were tested for cytotoxic activity.

International audience; Albendazole (ABZ) exhibits a potent antiparasitic activity against a broad spectrum of parasites. Unfortunately, the very low water solubility of ABZ (0.2 μg mL(-1), 0.7 μM) impairs considerably its formulation. Phase solubility diagrams showed that α-cyclodextrin (10% w/w), hydroxypropyl-β-cyclodextrin (40% w/w) and sulfobutylether-β-cyclodextrin (40% w/w) allowed an increase of apparent solubility with enhancement factors of 570, 3970, and 5880, respectively. The apparent aqueous solubility of ABZ was markedly increased from 0.2 μg mL(-1) (0.7 μM) without cyclodextrins to 1.52 mg mL(-1) (5.69 mM) with random methyl-β-cyclodextrin (Me-β-CD) (40% w/w). This corresponds to an apparent solubility enhancement factor of 7600 which is the maximal enhancement factor of ABZ apparent aqueous solubility ever reported in the literature using conventional cyclodextrins. The complexation mechanism between ABZ and cyclodextrins has been investigated using phase solubility diagrams, nuclear magnetic resonance ((1)H NMR) coupled with two-dimensional nuclear Overhauser effect (NOESY) experiments and molecular docking calculations. The results showed that the central bicyclic fragment from ABZ interacts with Me-β-CD according to 1:1 stoichiometry.

Because NO is not very reactive in an oxygen-free buffer, a significant part of serotonin (5-HT) is transformed by NO in nondeaerated phosphate buffer, at pH 7.4, into (4-serotonyl)-4-serotonin, 4-nitrososerotonin, and 4-nitroserotonin. Dimerization and above all nitrosation occur through the HNO2 reaction in the pH 4-6 range, possibly via radical mechanism involving N2O3. 5-HT is readily a substrate for nitrosation by HNO2 or N2O3, whereas tyrosine was described as not very reactive under the same conditions. Peroxynitrite converts 5-HT to the (4-serotonyl)-4-serotonin and to the 4-nitro derivative. In order to evaluate whether such structural modifications could modulate the biological properties of 5-HT, arterial pressure was measured after i.v. bolus injection of these derivatives to anesthetized rats. Injections of the 4-nitroso- and 4-nitro-5-HT resulted in first a brief hypotensive response and did not give the subsequent hypertensive and hypotensive phases observed with 5-HT. Finally, when tested on some cloned rat 5-HT receptors stably transfected into LMTK- cells, both 4-nitroso and 4-nitro derivatives behaved as agonists and antagonists toward 5-HT1B and 5-HT2B receptors, respectively.

Five known indole alkaloids, (+)-quebrachamine, (−)-eburnamine, (+)-isoeburnamine, (−)-eburnaminol and (+)-larutensine, and two new alkaloids, terengganensines A 1 and B 2, possessing a unique dihydroeburnane skeleton were isolated from the bark of Kopsia terengganensis. The structures of the new compounds were elucidated by spectral methods.