Synthesis and cytotoxicity evaluation of d- and l-sugar-containing mono- and bidesmosidic ursane-type saponins.

Ursolic acid and uvaol are naturally occurring triterpenoids that exhibit a broad spectrum of pharmacological activities, including cytotoxicity. However, a primary challenge in the development of ursane-type pentacyclic triterpenoids for pharmacological use is their poor aqueous solubility, which can impede their effectiveness as therapeutics agents. In this study, we present the facile synthesis of ursolic acid monodesmosides and uvaol bidesmosides, incorporating naturally occurring and water-soluble pentoses and deoxyhexose sugar moieties of opposite d- and l-configurations at the C3 or C3/C28 positions of the ursane core. The twenty synthetic saponins were evaluated in vitro for their cytotoxicity against lung carcinoma (A549) and colorectal adenocarcinoma (DLD-1) cell lines. Notably, all the bidesmosidic uvaol saponins were shown to be cytotoxic as compared to their non-cytotoxic parent triterpenoid. For each series of ursane-type saponins, the most active compounds were 3-O-α-l-arabinopyranosyl ursolic acid (3h) and 3,28-di-O-α-l-rhamnopyranosyl uvaol (4f), showing IC50 values in the low micromolar range against A549 and DLD-1 cancer lines.

Structural characterization of a nonionic rhamnolipid from Burkholderia lata.

We present the isolation and structural characterization of a novel nonionic dirhamnolipid methyl ester produced by the bacterium Burkholderia lata. The structure and the absolute configuration of the isolated dirhamnolipid bearing a symmetrical C14-C14 methyl ester chain were thoroughly investigated through chemical degradation and spectroscopic methods including 1D and 2D NMR analysis, HR-ESI-TOF-MS, chiral GC-MS, and polarimetry. Our work represents the first mention in the literature of a rhamnolipid methyl ester from Burkholderia species.

C7 Epimerization of Benzylidene-Protected ß-d-Idopyranosides Brings Structural Insights into Idose Conformational Flexibility.

Idose is unique among other aldohexoses because of its high conformational flexibility in solution. We herein show that benzylidene acetal-protected 3-O-acyl-ß-d-idopyranosides undergo Lewis acid-catalyzed C7 epimerization with concomitant 4C1 to 1C4 ring inversion. The reaction conditions and structural parameters for this transformation to occur have been thoroughly investigated through an extensive glycosylation study combined with NMR analyses, X-ray diffraction, and quantum molecular modeling. In addition to reporting a direct, ß-stereoselective idosylation approach, our work brings fundamental structural insights into the conformational flexibility of idose.

Total synthesis, isolation, surfactant properties, and biological evaluation of ananatosides and related macrodilactone-containing rhamnolipids.

Rhamnolipids are a specific class of microbial surfactants, which hold great biotechnological and therapeutic potential. However, their exploitation at the industrial level is hampered because they are mainly produced by the opportunistic pathogen Pseudomonas aeruginosa. The non-human pathogenic bacterium Pantoea ananatis is an alternative producer of rhamnolipid-like metabolites containing glucose instead of rhamnose residues. Herein, we present the isolation, structural characterization, and total synthesis of ananatoside A, a 15-membered macrodilactone-containing glucolipid, and ananatoside B, its open-chain congener, from organic extracts of P. ananatis. Ananatoside A was synthesized through three alternative pathways involving either an intramolecular glycosylation, a chemical macrolactonization or a direct enzymatic transformation from ananatoside B. A series of diasteroisomerically pure (1→2), (1→3), and (1→4)-macrolactonized rhamnolipids were also synthesized through intramolecular glycosylation and their anomeric configurations as well as ring conformations were solved using molecular modeling in tandem with NMR studies. We show that ananatoside B is a more potent surfactant than its macrolide counterpart. We present evidence that macrolactonization of rhamnolipids enhances their cytotoxic and hemolytic potential, pointing towards a mechanism involving the formation of pores into the lipidic cell membrane. Lastly, we demonstrate that ananatoside A and ananatoside B as well as synthetic macrolactonized rhamnolipids can be perceived by the plant immune system, and that this sensing is more pronounced for a macrolide featuring a rhamnose moiety in its native 1 C 4 conformation. Altogether our results suggest that macrolactonization of glycolipids can dramatically interfere with their surfactant properties and biological activity.

Development and characterisation of a nanostructured hybrid material with vitamin B12 and bagasse-derived activated carbon for anaerobic chlordecone (Kepone) removal.

Intensive use of the chlorinated pesticide chlordecone from the 1970s to 1993 to prevent crop damage in banana plantations of Guadeloupe and Martinique led to diffuse pollution of soils and surface waters, affecting both fauna and human beings in the contaminated areas. Since 2001, drinking water production plants have been equipped with filters containing activated carbon that must be treated after saturation. The objective of this work is to produce a hybrid material composed of activated carbon and vitamin B12 (VB12) for the degradation of chlordecone (CLD). The preparation of such a hybrid material is carried out by non-covalent fixation to achieve an eco-friendly solution for the serious environmental problem of contamination by chlorinated pesticides. It is thus proposed to degrade CLD by a physico-chemical treatment allowing salvage of the catalyst, which is adsorbed on the carbon surface to generate less waste that is inexpedient to treat. Activated carbon (AC) is produced locally from available sugarcane bagasse subjected to phosphoric acid activation. The main characteristics of this material are a major mesoporous structure (0.91%) and a specific (BET) surface area ranging from 1000 to 1500 m2 g-1. The experimental results showed that BagP1.5 has a high adsorption capacity for VB12 due to its large surface area (1403 m2 g-1). The binding of VB12 to the bagasse-derived AC is favoured at high temperatures. The adsorption is optimal at a pH of approximately 6. The maximum adsorption capacity of VB12 on the AC, deduced from the Langmuir model, was 306 mg g-1, confirming the high affinity between the two components. The hybrid material was characterised by FTIR, Raman, X-ray fluorescence spectroscopy and SEM analysis. CLD removal by this hybrid material was faster than that by VB12 or BagP1.5 alone. The CLD degradation products were characterised by mass spectrometry.

Peyssonnosides A-B, Unusual Diterpene Glycosides with a Sterically Encumbered Cyclopropane Motif: Structure Elucidation Using an Integrated Spectroscopic and Computational Workflow.

Two sulfated diterpene glycosides featuring a highly substituted and sterically encumbered cyclopropane ring have been isolated from the marine red alga Peyssonnelia sp. Combination of a wide array of 2D NMR spectroscopic experiments, in a systematic structure elucidation workflow, revealed that peyssonnosides A-B (1-2) represent a new class of diterpene glycosides with a tetracyclo [7.5.0.01,10.05,9] tetradecane architecture. A salient feature of this workflow is the unique application of quantitative interproton distances obtained from the rotating frame Overhauser effect spectroscopy (ROESY) NMR experiment, wherein the ß-d-glucose moiety of 1 was used as an internal probe to unequivocally determine the absolute configuration, which was also supported by optical rotatory dispersion (ORD). Peyssonnoside A (1) exhibited promising activity against liver stage Plasmodium berghei and moderate antimethicillin-resistant Staphylococcus aureus (MRSA) activity, with no cytotoxicity against human keratinocytes. Additionally, 1 showed strong growth inhibition of the marine fungus Dendryphiella salina indicating an antifungal ecological role in its natural environment. The high natural abundance and novel carbon skeleton of 1 suggests a rare terpene cyclase machinery, exemplifying the chemical diversity in this phylogenetically distinct marine red alga.

Antibacterial Oligomeric Polyphenols from the Green Alga Cladophora socialis.

A series of oligomeric phenols including the known natural product 3,4,3',4'-tetrahydroxy-1,1'-biphenyl (3), the previously synthesized 2,3,8,9-tetrahydroxybenzo[ c]chromen-6-one (4), and eight new related natural products, cladophorols B-I (5-12), were isolated from the Fijian green alga Cladophora socialis and identified by a combination of NMR spectroscopy, mass spectrometric analysis, and computational modeling using DFT calculations. J-resolved spectroscopy and line width reduction by picric acid addition aided in resolving the heavily overlapped aromatic signals. A panel of Gram-positive and Gram-negative pathogens used to evaluate pharmacological potential led to the determination that cladophorol C (6) exhibits potent antibiotic activity selective toward methicillin-resistant Staphylococcus aureus (MRSA) with an MIC of 1.4 µg/mL. Cladophorols B (5) and D-H (7-11) had more modest but also selective antibiotic potency. Activities of cladophorols A-I (4-12) were also assessed against the asexual blood stages of Plasmodium falciparum and revealed cladophorols A (4) and B (5) to have modest activity with EC50 values of 0.7 and 1.9 µg/mL, respectively.

Structural determination of ananatoside A: An unprecedented 15-membered macrodilactone-containing glycolipid from Pantoea ananatis.

The bacterium Pantoea ananatis was reported to produce glycolipid biosurfactants of unknown structures. Herein, we present the isolation and structural determination of ananatoside A, the main congener of a new family of 15-membered macrodilactone-containing glucolipids. The structure of ananatoside A was elucidated via chemical degradation and spectroscopic methods including 1D/2D NMR analysis, tandem MS/MS, GC-MS, HR-ESI-TOF-MS, MALDI-TOF-MS, and polarimetry. Computational methods were used to predict the most abundant conformers of ananatoside A.

Synthesis, cytotoxicity and anti-inflammatory activity of rhamnose-containing ursolic and betulinic acid saponins.

Betulinic acid and ursolic acid are ubiquitous, naturally-occurring triterpenoids exhibiting various pharmacological activities including cytotoxic and anti-inflammatory activities. However, these triterpenoids display unfavorable pharmacokinetic properties as well as low aqueous solubility. It has been shown that the presence of α-l-rhamnose moieties positively modulates the anticancer activity of secondary metabolites. Herein we report the synthesis and in vitro evaluation of cytotoxic and anti-inflammatory activities of a series of rhamnose-containing ursolic and betulinic acid saponins. Relying on Schmidt's normal and inverse procedures, monorhamnosides, (1→4)-linked dirhamnosides as well as branched trirhamnosides and tetrarhamnosides were synthesized in high yields with full control of stereoselectivity. A betulinic acid saponin bearing a 3-O-α-l-rhamnopyranosyl-(1→4)-α-l-rhamnopyranosyl residue was found to be a potent cytotoxic agent against human colorectal adenocarcinoma cells without damaging the healthy cells (selectivity ratio > 20) whereas rhamnose-containing ursolic acid saponins potently inhibited NO overproduction induced by LPS-stimulated macrophages. Our results reveal that rhamnose-containing ursolic and betulinic acid saponins represent promising therapeutic agents.

Correction: Recent trends in the structural revision of natural products.

Correction for 'Recent trends in the structural revision of natural products' by Bhuwan Khatri Chhetri et al., Nat. Prod. Rep., 2018, 35, 514-531.

Recent trends in the structural revision of natural products.

Covering: 2012 to 2017 This article reviews recent reports on the structural revision of natural products. Through a critical assessment of the original and revised published structures, the article addresses why each structure was targeted for revision, discusses the techniques and key discrepancies that led to the proposal of the revised structure, and offers measures that may have been taken during the original structure determination to prevent error. With the revised structures in hand, weaknesses of original proposals are assessed, providing a better understanding on the logic behind structure determination.

Chemical encoding of risk perception and predator detection among estuarine invertebrates.

An effective strategy for prey to survive in habitats rich in predators is to avoid being noticed. Thus, prey are under selection pressure to recognize predators and adjust their behavior, which can impact numerous community-wide interactions. Many animals in murky and turbulent aquatic environments rely on waterborne chemical cues. Previous research showed that the mud crab, Panopeus herbstii, recognizes the predatory blue crab, Callinectus sapidus, via a cue in blue crab urine. This cue is strongest if blue crabs recently preyed upon mud crabs. Subsequently, mud crabs suppress their foraging activity, reducing predation by blue crabs. Using NMR spectroscopy- and mass spectrometry-based metabolomics, chemical variation in urine from blue crabs fed different diets was related to prey behavior. We identified the urinary metabolites trigonelline and homarine as components of the cue that mud crabs use to detect blue crabs, with concentrations of each metabolite dependent on the blue crab's diet. At concentrations found naturally in blue crab urine, trigonelline and homarine, alone as well as in a mixture, alerted mud crabs to the presence of blue crabs, leading to decreased foraging by mud crabs. Risk perception by waterborne cues has been widely observed by ecologists, but the molecular nature of these cues has not been previously identified. Metabolomics provides an opportunity to study waterborne cues where other approaches have historically failed, advancing our understanding of the chemical nature of a wide range of ecological interactions.

Iodinated Meroditerpenes from a Red Alga Callophycus sp.

Unique iodine-containing meroditerpenes iodocallophycoic acid A (1) and iodocallophycols A-D (2-5) were discovered from the Fijian red alga Callophycus sp. Because flexibility of the molecular skeleton impaired full characterization of relative stereochemistries by NMR spectroscopy, a DFT-based theoretical model was developed to derive relevant interproton distances which were compared to those calculated from NOE measurements, yielding the relative stereochemistries. The correct 2S,6S,7S,10S,14S enantiomers were then identified by comparison of theoretical and experimental ECD spectra. Biological activities of these iodinated and brominated meroditerpenes and additional new, related bromophycoic acid F (6) and bromophycoic acid A methyl ester (7), were evaluated for relevant human disease targets. Iodocallophycoic acid A (1) showed moderate antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) with MIC values of 1.4 and 2.2 µg mL-1, respectively. It also potentiated the anti-MRSA activity of oxacillin in a synergistic fashion, resulting in an 8-fold increase in oxacillin potency, for a MIC of 16 µg mL-1.

Chemical composition and anti-herpes simplex virus type 1 (HSV-1) activity of extracts from Cornus canadensis.

BACKGROUND: Many plants of boreal forest of Quebec have been used by Native Americans to treat a variety of microbial infections. However, the antiviral activities of these plants have been seldom evaluated on cellular models to validate their in vitro efficiencies. In this study, Cornus canadensis L. (Cornaceae), a plant used in Native American traditional medicine to treat possible antiviral infections, has been selected for further examination. METHODS: The plant was extracted by decoction and infusion with water, water/ethanol 1:1 and ethanol to obtain extracts similar to those used by Native Americans. The effects of the extracts were tested on herpes simplex virus type-1 (HSV-1) using a plaque reduction assay. Moreover, bioassay-guided fractionation was achieved to isolate bioactive compounds. RESULTS: Water/ethanol 1:1 infusion of C. canadensis leaves were the most active extracts to inhibit virus absorption with EC50 of about 9 µg mL-1, whereas for direct mode, both extraction methods using water or water/ethanol 1:1 as solvent were relatively similar with EC50 ranging from 11 to 17 µg mL-1. The fractionation led to the identification of active fractions containing hydrolysable tannins. Tellimagrandin I was found the most active compound with an EC50 of 2.6 µM for the direct mode and 5.0 µM for the absorption mode. CONCLUSION: Altogether, the results presented in this work support the antiviral activity of Cornus canadensis used in Native American traditional medicine.

4'-Methoxyphenacyl-Assisted Synthesis of ß-Kdo Glycosides.

3-Deoxy-ß-d-manno-oct-2-ulosonic acid (ß-Kdo) glycosides are mainly found in capsular polysaccharides and extracellular exopolysaccharides from Gram-negative bacteria. These compounds have profound biological implications in immune response and act as virulence factors. We have developed a novel methodology for the stereoselective synthesis of ß-Kdo glycosides via the use of a 4'-methoxyphenacyl (Phen) auxiliary group at the C1 position of a peracetylated ß-Kdo thioglycoside. Under the promotion of NIS/AgOTf in acetonitrile, a series of Kdo glycosides was synthesized in good yield and ß-selectivity while minimizing the formation of undesirable glycals. Stereoselectivity of the glycosylation was shown to be modulated by various factors such as promotor, solvent, anomeric ratio of donor, nature of acceptor, and Phen substitution. Chemoselective cleavage of the Phen group was performed under the action of Zn/HOAc. DFT calculations together with experimental results suggested that α-triflate and a six-membered α-spiroPhen are plausible intermediates of the reaction, accounting for the enhanced formation of ß-Kdo glycosides. The developed methodology could be applied to the synthesis of ß-Kdo-containing glycans from pathogenic bacteria.

Structure elucidation of anti-methicillin resistant Staphylococcus aureus (MRSA) flavonoids from balsam poplar buds.

There is nowadays an urgent need for developing novel generations of antibiotic agents due to the increased resistance of pathogenic bacteria. As a rich reservoir of structurally diverse compounds, plant species hold promise in this regard. Within this framework, we isolated a unique series of antibacterial flavonoids, named balsacones N-U, featuring multiple cinnamyl chains on the flavan skeleton. The structures of these compounds, isolated as racemates, were determined using extensive 1D and 2D NMR analysis in tandem with HRMS. Balsacones N-U along with previously isolated balsacones A-M were evaluated for their antibacterial activity against clinical isolates of methicillin resistant Staphylococcus aureus (MRSA). Several of the tested balsacones were potent anti-MRSA agents showing MIC values in the low micromolar range. Structure-activity relationships study highlighted some important parameters involved in the antibacterial activity of balsacones such as the presence of cinnamyl and cinnamoyl chains at the C-3 and C-8 positions of the flavan skeleton, respectively. These results suggest that balsacones could represent a potential novel class of naturally occurring anti-MRSA agents.

DFT Calculations and ROESY NMR Data for the Diastereochemical Characterization of Cytotoxic Tetraterpenoids from the Oleoresin of Abies balsamea.

Eight non-carotenoid tetraterpenoids, abibalsamins C-J (3-10), were isolated from the oleoresin of Abies balsamea. Their chemical structures were determined based on analysis of 1D/2D NMR and MS data. The assignment of their relative configurations was accomplished using homonuclear coupling constants in tandem with ROESY data. However, the presence of two stereogenic centers on a flexible side chain complicated the characterization. In silico models and ROESY data were analyzed in order to assign relative configurations of the isolated tetraterpenoids. Abibalsamins B and H-J showed moderate cytotoxicity against human A549 lung carcinoma cells, with IC50 values ranging between 6.7 and 10 µM.

Antibacterial Balsacones J-M, Hydroxycinnamoylated Dihydrochalcones from Populus balsamifera Buds.

A phytochemical investigation of buds from the hardwood tree Populus balsamifera led to the isolation of six new cinnamoylated dihydrochalcones as pairs of racemates and one as a racemic mixture along with the known compound iryantherin-D (2), the absolute configuration of which was determined for the first time. The structures of balsacones J (1), K (3), L (4), and M (5) were elucidated on the basis of spectroscopic data (1D and 2D NMR, IR, and MS). Chiral HPLC separations were carried out, and the absolute configuration of the isolated enantiomers unambiguously established via X-ray diffraction analyses and electron circular dichroism spectroscopic data. Each of the purified enantiomers exhibited potent in vitro antibacterial activity against Staphylococcus aureus with IC50 values ranging from 0.61 to 6 µM.

Isolation of a new disaccharide nucleoside from Helleborus caucasicus: structure elucidation and total synthesis of hellecaucaside A and its ß-anomer.

Hellecaucaside A, a new disaccharide nucleoside featuring a 2'-O-α-D-ribofuranosyluridine skeleton and a 4-hydroxybenzoyl group at the 5' position, was isolated from the underground part of Helleborus caucasicus. The structure of the compound was elucidated by means of chemical degradation and spectroscopic analyses, such as 1D/2D NMR, chiral-GC, and HRMS. The total synthesis of hellecaucaside A and its ß-anomer was accomplished, unequivocally confirming the structure of the natural product.