First Occurrence of Megastigmane Glucosides in a Plant of Retama Genus.

Chemical investigation of Retama sphaerocarpa collected in Algeria resulted in the isolation of two megastigmane glucosides, compounds 1 and 2, along with a series of isoflavones and phenol derivatives. Compound 1, named retamoside, was new and its structure was determined by extensive application of spectroscopic methods, including HRMS, 1D and 2D NMR and CD. The anti-inflammatory properties of co-occurring main megastigmane, saurobaccioside B (2) and structurally related vomifoliol (3) on LPS-stimulated murine macrophages RAW 274.7 have been evaluated.

Sesquiterpene Lactones with the 12,8-Guaianolide Skeleton from Algerian Centaurea omphalotricha.

In continuing our investigation on the chemical diversity of Algerian plants, we examined Centaurea omphalotricha, whose chemical composition has been poorly studied. The present work was aimed at characterizing the secondary metabolite pattern of the CHCl3 extract of the aerial parts of this plant that displayed antiproliferative properties in a preliminary screening on HeLa cell line. The chemical analysis led us to characterize the bioactive oxygenated terpenoid fraction which includes, within major known metabolites, two new minor sesquiterpene lactones, centaurolide-A (1) and centaurolide-B (2). The structures of two compounds exhibiting the 12,8-guaianolide skeleton were determined by spectroscopic methods as well as by chemical correlation with inuviscolide (3), a well-known bioactive guaianolide isolated from Dittrichia (=Inula) viscosa. Centaurolides A and B represent the first report of 8,12-guaianolide skeleton in Centaurea genus. The effect of new compounds 1 and 2 and inuviscolide (3) on HeLa cell has also been evaluated.

The chemical and chemo-ecological studies on Weizhou nudibranch Glossodoris atromarginata.

A detailed chemical investigation of the nudibranch Glossodoris atromarginata collected from Weizhou Island, South China Sea, yielded a new spongian-type diterpene 1, together with the four known-related compounds 2-5. The structure of the new compound 1 was elucidated by the detailed spectroscopic analysis, the comparison of the spectroscopic data with the known diterpene isoagatholactone, and the 13 C chemical shift calculation. In addition, evidence for the absolute stereochemistry of the known compound 2 was, for the first time, provided by the application of time-dependent density functional theory electronic circular dichroism calculation.

A new bis-γ-pyrone polypropionate of onchidiol family from marine pulmonate mollusk Onchidium sp.

A new bis-γ-pyrone polypropionate, 4,16-di-epi-onchidiol (1), along with three known related compounds (2-4) were isolated from the marine pulmonate mollusk Onchidium sp. The structure of compound 1 was elucidated by extensive spectroscopic analysis and by comparison the NMR data with its stereoisomers 2-4, whereas its absolute configuration was determined by the combination of X-ray diffraction analysis and TDDFT-ECD calculation. In bioassay, the isolated compounds exhibited broad cytotoxicity against several cancer cell lines with IC50 values ranging from 24.6 to 88.5µM.

Amphilectene Diterpene Isonitriles and Formamido Derivatives from the Hainan Nudibranch Phyllidia Coelestis.

Terpene content of two distinct collections of the nudibranch Phyllidia coelestis from the South China Sea has been chemically analyzed. A series of amphilectene diterpenes, most likely of dietary origin, with isocyano and formamido functionalities have been isolated from both collections and spectroscopically characterized by an exhaustive nuclear magnetic resonance (NMR) analysis. Interestingly, the structural architecture of compounds 5-7 and 9 with both 8,13-cis and 12,13-cis ring junctions is unprecedented in the amphilectene skeleton. Metabolite 3, which was the most abundant in the nudibranch's mantle, has been shown to deter feeding by a generalist predator, supporting its involvement in chemical defense.

In Silico Identification and Experimental Validation of (-)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator.

The nuclear receptors (NRs) RARα, RXRα, PPARα, and PPARγ represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search for molecules able to simultaneously target all the above-mentioned NRs, we screened an in-house developed molecular database using a ligand-based approach, identifying (-)-Muqubilin (Muq), a cyclic peroxide norterpene from a marine sponge, as a potential hit. The ability of this compound to stably and effectively bind these NRs was assessed by molecular docking and molecular dynamics simulations. Muq recapitulated all the main interactions of a canonical full agonist for RXRα and both PPARα and PPARγ, whereas the binding mode toward RARα showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXRα, PPARα, and PPARγ with an activity in the low- to sub-micromolar range. On the other hand, in the case of RAR, a very weak agonist activity was observed in the micromolar range. Quite surprisingly, we found that Muq is a positive allosteric modulator for RARα, as both luciferase assays and in vivo analysis using a zebrafish transgenic retinoic acid (RA) reporter line showed that co-administration of Muq with RA produced a potent synergistic enhancement of RARα activation and RA signaling.

Cytotoxic Nitrogenous Terpenoids from Two South China Sea Nudibranchs Phyllidiella pustulosa, Phyllidia coelestis, and Their Sponge-Prey Acanthella cavernosa.

A detailed chemical investigation of two South China Sea nudibranchs Phyllidiella pustulosa and Phyllidia coelestis, as well as their possible sponge-prey Acanthella cavernosa, led to the isolation of one new nitrogenous cadinane-type sesquiterpenoid xidaoisocyanate A (1), one new naturally occurring nitrogen-containing kalihinane-type diterpenoid bisformamidokalihinol A (16), along with 17 known nitrogenous terpenoids (2⁻15, 17⁻19). The structures of all the isolates were elucidated by detailed spectroscopic analysis and by the comparison of their spectroscopic data with those reported in the literature. In addition, the absolute stereochemistry of the previously reported axiriabiline A (5) was determined by X-ray diffraction (XRD) analysis. In a bioassay, the bisabolane-type sesquiterpenoids 8, 10, and 11 exhibited cytotoxicity against several human cancer cell lines.

Sarinfacetamides A and B, Nitrogenous Diterpenoids with Tricyclo[6.3.1.01,5]dodecane Scaffold from the South China Sea Soft Coral Sarcophyton infundibuliforme.

Two novel nitrogenous diterpenoids, sarinfacetamides A (1) and B (2), featuring an uncommon tricyclo[6.3.1.01,5]dodecane scaffold, and a known related diterpene (3) were isolated from the South China Sea soft coral Sarcophyton infundibuliforme. Their structures, including the absolute configuration of 1, were established by extensive spectroscopic analysis and TDDFT-ECD calculation. Compounds 1 and 3 exhibited interesting promotion effects on the ConA-induced T lymphocyte proliferation. A plausible biosynthetic pathway for 1 and 2 was also proposed.

Marine bis-γ-pyrone polypropionates of onchidione family and their effects on the XBP1 gene expression.

Two additional new members of the onchidione family, 16-epi-onchidione (1) and 4-epi-onchidione (2), co-occurring with six previously reported bis-γ-pyrone polypropionates including onchidione (3), were isolated from the marine pulmonate Onchidium sp. Their structures were determined by extensive spectroscopic analysis and by comparison with 3 and onchidione-related derivatives. The absolute configuration of 1 was established by X-ray diffraction analysis employing graphite monochromated Cu Kα radiation (λ = 0.71073 Å) with small Flack parameter 0.08. In addition, the absolute stereochemistry of previously reported onchidionol (6) was confirmed by the X-ray diffraction analysis. Some of the isolated compounds showed significant activation effects on the splicing of XBP1 mRNA as ER stress modulators to inhibit the growth of tumors.

Prenylated Flavonoids and Phenolic Compounds from the Rhizomes of Marine Phanerogam Cymodocea nodosa.

Chemical investigation of the rhizomes of the marine phanerogam Cymodocea nodosa resulted in the isolation of two new prenylated flavon-di-O-glycosides, cymodioside A (1: ) and B (2: ), along with known phenolic compounds 3: -7: , some of which never reported from seagrasses to date. The structures of compounds 1: and 2: were established by extensive nuclear magnetic resonance analysis. In addition, the absolute configuration of 4-(2,5-dihydroxyhexyl) benzene-1,2-diol (7: ), which was not previously reported in the literature, has been now determined.

Chemistry of Two Distinct Aeolid Spurilla Species: Ecological Implications.

The lipophilic extracts of two marine aeolid nudibranch molluscs of the genus Spurilla collected in distinct geographical areas have been chemically analyzed. The Et2 O extracts of the nudibranchs were dominated by the presence of usual fatty acids and sterols and contained terpenoid compounds 1 - 3 as minor metabolites. Spurillin A (1) and spurillin B (3) were new molecules whereas cis-γ-monocyclofarnesol (2) was already reported in the literature as a synthesis product. Interestingly, bursatellin (4), previously isolated from anaspidean molluscs of the genus Bursatella, was found in the butanol extract of both Spurilla species. Compounds 1 - 4 were not detected in the extracts of the sea-anemone preys collected together with the molluscs.

Marine Terpenoid Diacylguanidines: Structure, Synthesis, and Biological Evaluation of Naturally Occurring Actinofide and Synthetic Analogues.

A new diacylguanidine, actinofide (1), has been isolated from the marine mollusk Actinocyclus papillatus. The structure, exhibiting a guanidine moiety acylated by two terpenoid acid units, has been established by spectroscopic methods and secured by synthesis. Following this, a series of structural analogues have been synthesized using the same procedure. All of the compounds have been evaluated in vitro for the growth inhibitory activity against a variety of cancer cell lines.

Volatile secondary metabolites as aposematic olfactory signals and defensive weapons in aquatic environments.

Olfaction is considered a distance sense; hence, aquatic olfaction is thought to be mediated only by molecules dissolved in water. Here, we challenge this view by showing that shrimp and fish can recognize the presence of hydrophobic olfactory cues by a "tactile" form of chemoreception. We found that odiferous furanosesquiterpenes protect both the Mediterranean octocoral Maasella edwardsi and its specialist predator, the nudibranch gastropod Tritonia striata, from potential predators. Food treated with the terpenes elicited avoidance responses in the cooccurring shrimp Palaemon elegans Rejection was also induced in the shrimp by the memory recall of postingestive aversive effects (vomiting), evoked by repeatedly touching the food with chemosensory mouthparts. Consistent with their emetic properties once ingested, the compounds were highly toxic to brine shrimp. Further experiments on the zebrafish showed that this vertebrate aquatic model also avoids food treated with one of the terpenes, after having experienced gastrointestinal malaise. The fish refused the food after repeatedly touching it with their mouths. The compounds studied thus act simultaneously as (i) toxins, (ii) avoidance-learning inducers, and (iii) aposematic odorant cues. Although they produce a characteristic smell when exposed to air, the compounds are detected by direct contact with the emitter in aquatic environments and are perceived at high doses that are not compatible with their transport in water. The mouthparts of both the shrimp and the fish have thus been shown to act as "aquatic noses," supporting a substantial revision of the current definition of the chemical senses based upon spatial criteria.

Structure-activity relationships of fraxamoside as an unusual xanthine oxidase inhibitor.

Fraxamoside, a macrocyclic secoiridoid glucoside featuring a hydroxytyrosol group, was recently identified as a xanthine oxidase inhibitor (XOI) comparable in potency in vitro to the standard antigout drug allopurinol. However, this activity and its considerably higher value than its derivatives oleuropein, oleoside 11-methyl ester, and hydroxytyrosol are not explained by structure-activity relationships (SARs) of known XOIs. To exclude allosteric mechanisms, we first determined the inhibition kinetic of fraxamoside. The resulting competitive mechanism prompted a computational SAR characterization, combining molecular docking and dynamics, which fully explained the behavior of fraxamoside and its derivatives, attributed the higher activity of the former to conformational properties of its macrocycle, and showed a substantial contribution of the glycosidic moiety to binding, in striking contrast with glycoside derivatives of most other XOIs. Overall, fraxamoside emerged as a lead compound for a new class of XOIs potentially characterized by reduced interference with purine metabolism.

Exploring the Bioactive Terpenoid Content of an Algerian Plant of the Genus Pulicaria: The ent-Series of Asteriscunolides.

Chemical analysis of the chloroform extract of the aerial parts of the Algerian plant Pulicaria undulata exhibiting anti-inflammatory activity resulted in the isolation of 10 new humulene sesquiterpenoids, 1-10, belonging to the asteriscunolide family of compounds. The structure and relative configuration have been defined by NMR data, whereas the absolute configuration has been established by ECD analysis. Compounds 1-10 include enantiomers of the known asteriscunolides A-D and tetrahydroasteriscunolide previously reported from the genera Asteriscus and Nauplius. Compounds 1 and 10 showed in vitro anti-inflammatory activity by inhibiting heat-induced albumin denaturation with IC50 values of 23.76 and 220.42 µM.

Exploring the Chemical Diversity of Algerian Plants: Three New Pentacyclic Triterpenoids from Launaea acanthoclada Roots.

The chemical study of Launaea acanthoclada from South-East Algeria led to the isolation of twelve oxygenated terpenoid compounds, including three new pentacyclic triterpenoids 1-3 with either lupane or ursane rearranged skeletons. The structure and the stereochemistry of these compounds were established by spectroscopic methods, including NMR techniques. The chemical pattern of L. acanthoclada is in accordance with the triterpenoid scenario of the genus Launaea embracing to date lupane, oleane, ursane and taraxastane skeletons. However, the carbon frameworks exhibited by new compounds 1-3 have never been reported from Launaea species.

Marine Mollusk-Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance.

The chemical investigation of marine mollusks has led to the isolation of a wide variety of bioactive metabolites, which evolved in marine organisms as favorable adaptations to survive in different environments. Most of them are derived from food sources, but they can be also biosynthesized de novo by the mollusks themselves, or produced by symbionts. Consequently, the isolated compounds cannot be strictly considered as "chemotaxonomic markers" for the different molluscan species. However, the chemical investigation of this phylum has provided many compounds of interest as potential anticancer drugs that assume particular importance in the light of the growing literature on cancer biology and chemotherapy. The current review highlights the diversity of chemical structures, mechanisms of action, and, most importantly, the potential of mollusk-derived metabolites as anticancer agents, including those biosynthesized by mollusks and those of dietary origin. After the discussion of dolastatins and kahalalides, compounds previously studied in clinical trials, the review covers potentially promising anticancer agents, which are grouped based on their structural type and include terpenes, steroids, peptides, polyketides and nitrogen-containing compounds. The "promise" of a mollusk-derived natural product as an anticancer agent is evaluated on the basis of its ability to target biological characteristics of cancer cells responsible for poor treatment outcomes. These characteristics include high antiproliferative potency against cancer cells in vitro, preferential inhibition of the proliferation of cancer cells over normal ones, mechanism of action via nonapoptotic signaling pathways, circumvention of multidrug resistance phenotype, and high activity in vivo, among others. The review also includes sections on the targeted delivery of mollusk-derived anticancer agents and solutions to their procurement in quantity.

In Vitro Growth Inhibitory Activities of Natural Products from Irciniid Sponges against Cancer Cells: A Comparative Study.

Marine sponges of the Irciniidae family contain both bioactive furanosesterterpene tetronic acids (FTAs) and prenylated hydroquinones (PHQs). Both classes of compounds are known for their anti-inflammatory, antioxidant, and antimicrobial properties and known to display growth inhibitory effects against various human tumor cell lines. However, the different experimental conditions of the reported in vitro bioassays, carried out on different cancer cell lines within separate studies, prevent realistic actual discrimination between the two classes of compounds from being carried out in terms of growth inhibitory effects. In the present work, a chemical investigation of irciniid sponges from Tunisian coasts led to the purification of three known FTAs and three known PHQs. The in vitro growth inhibitory properties of the six purified compounds have been evaluated in the same experiment in a panel of five human and one murine cancer cell lines displaying various levels of sensitivity to proapoptotic stimuli. Surprisingly, FTAs and PHQs elicited distinct profiles of growth inhibitory-responses, differing by one to two orders of magnitude in favor of the PHQs in all cell lines. The obtained comparative results are discussed in the light of a better selection of drug candidates from natural sources.

Phytochemical Study of Eryngium triquetrum: Isolation of Polyacetylenes and Lignans.

Phytochemical investigation of the ethyl acetate extract from the aerial parts of Eryngium triquetrum Vahl resulted in the isolation of new polyacetylenes, triquetridiol (6) and trans-epoxy-triquetrol (7a/7b, diastereomeric mixture), and the lignan demethoxy carolignan Z (8a/8b, erythro/threo pair), together with a series of related known metabolites. Additionally, some already reported phenolic and flavonoid compounds were also identified in the extract. Structural elucidation of the new compounds was made by spectroscopic analysis, mainly NMR and mass spectrometry. To the best of our knowledge, this is the first report of polyacetylenes and lignans from E. triquetrum.

Is phototridachiahydropyrone a true natural product?

Abstract The occurrence of (−)-phototridachiahydropyrone (5) in nature has been proven. This compound has been now identified as minor component of the extract of marine sacoglossan mollusk Elysia crispata from which the main (−)-tridachiahydropyrone (4) was previously described. Synthetic (±)-5 was formerly obtained by Moses’ group by biomimetic photochemical conversion of (±)-tridachiahydropyrone (4). The same authors suggested that compound 5 had to be a natural product derived from precursor 4 “yet to be discovered”. Comparison of CD profiles of natural (−)-4 and (−)-5 indicated the same absolute configuration for both compounds. This evidence is in agreement with the concerted mechanism proposed for the photochemical conversion.