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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.

The liposoluble extract of Galium brunneum aerial parts from North-eastern Algeria was chemically investigated. The EtOAc soluble portion contained a series of glycosyl cucurbitacins and sterols including three new glucosyl hydroperoxy sterols 1–3 among other phenolic components whereas the BuOH soluble fraction was dominated by glycosyl derivatives of flavonoids, iridoids and lignans, according to the chemistry reported in the literature for the genus Galium. The structure of new oxidized sterols 1–3 was determined by spectroscopic methods as well as by comparison with related known metabolites. Selected main compounds from both extracts, which revealed moderate antibacterial activities, were tested for their growth inhibitory properties against Gram-positive and Gram-negative bacteria. This is the first report of cucurbitacins in plants of genus Galium.

Two symmetrical diacylguanidines, triophamine (1) and limaciamine (2), have been found to occur in three Polyceridae nudibranchs from Canary Islands. These compounds were previously reported from taxonomically related species collected from distinct geographical areas. Due to the peculiar occurrence of 1 and 2 in Polyceridae nudibranchs and, in particular, exclusively in members of Polycerinae and Triophinae subfamilies, it should be suggested that these diacylguanidines are distinctive chemical markers of this group of nudibranchs.

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.

A new bis-gamma-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 88.5?M.

Two novel nitrogenous diterpenoids, sarinfacetamides A (1) and B (2), featuring an uncommon tricydo[6.3.1.0(1,5)]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.

Two new 5-alkylpyrrole-2-carboxaldehyde derivatives, mycalenitrile-15 (1) and mycalenitrile-16 (2), along with five known related ones (3-7), were isolated from the South China Sea sponge Mycale lissochela. The structures of the new compounds were elucidated on the basis of extensive spectroscopic analysis and by comparison of their NMR data with those reported in the literature. In bioassay, compounds 1 and 7 exhibited significant PTP1B (Protein-tyrosine phosphatase 1B, a recognized target for diabetes and obesity) inhibitory activities with IC50 values of 8.6 and 3.1 μmol/L, respectively. A preliminary SAR analysis of the isolated compounds with their PTP1B inhibitory effects was described.

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.

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.

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&ndash, 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&rsquo, s mantle, has been shown to deter feeding by a generalist predator, supporting its involvement in chemical defense.

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, 4,16-di

The nuclear receptors (NRs) RAR&alpha, RXR&alpha, PPAR&alpha, and PPAR&gamma, 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 (&minus, )-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 RXR&alpha, and both PPAR&alpha, whereas the binding mode toward RAR&alpha, showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXR&alpha, 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 RAR&alpha, 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 RAR&alpha, activation and RA signaling.

The secondary metabolite pattern of Eryngium tricuspidatum has been found to be dominated by C17 acetylene oxylipins, according to the chemistry reported in the literature for the genus Eryngium. Two new oxylipins, 11-acetoxy-falcarindiol (4) and 1,2-dihydro-11-acetoxy-falcarindiol (5) have been isolated, along with main related polyacetylenes 1–3 and the already known monoterpene aldehydes 6–10, from the petroleum ether extract of roots. The structure and the absolute configuration of compounds 4 and 5 have been determined by spectroscopic methods as well as by comparison with related known compounds. Polyacetylenes 1–4 inhibited significantly the in vitro growth of a series of cancer cell lines, ranging from 0.3 to 29 μM, whereas 5 was inactive., SCOPUS: ar.j, info:eu-repo/semantics/published

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&ndash, 15, 17&ndash, 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.

Heterobranchs are a fascinating group of marine mollusks that are recognized as an important source of bioactive natural products. Often, these molecules, which are either selected from the diet or de novo biosynthesized by the mollusks, play a fundamental role for their survival being utilized as defensive chemicals against predators. A summary of the studies carried out by our group, in the last decade, on heterobranchs is presented here. A number of new compounds exhibiting different molecular architectures have been chemically characterized. Some of them have also shown an interesting pharmacological potential. Some ecological studies that we conducted on selected species of heterobranchs are also reviewed.

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.

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.

Bioassay-guided fractionation of the CHCl3/MeOH extract of Elysia ornata mucus showing antifungal activity led us to isolate kahalalide F (KF) along with two unprecedented related peptides. The structures of kahalalide Z1 (1) and kahalalide Z2 (2), were established by combination of NMR spectroscopic and mass spectrometry data, also including Marfey amino acid analysis. Compounds 1 and 2 displayed significant antimicrobial properties against several fungal pathogens infesting economically important plants, food, and fish, and were also found to inhibit the in vitro growth of a series of cancer cell lines in a comparable fashion with KF.

Two novel nitrogenous diterpenoids, sarinfacetamides A (1) and B (2), featuring an uncommon tricyclo[6.3.1.0

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.

Multitargeting or polypharmacological approaches, looking for single chemical entities retaining the ability to bind two or more molecular targets, are a potentially powerful strategy to fight complex, multifactorial pathologies. Unfortunately, the search for multiligand agents is challenging because only a small subset of molecules contained in molecular databases are bioactive and even fewer are active on a preselected set of multiple targets. However, collections of natural compounds feature a significantly higher fraction of bioactive molecules than synthetic ones. In this view, we searched our library of 1175 natural compounds from marine sources for molecules including a 2-aminoimidazole+aromatic group motif, found in known compounds active on single relevant targets for Alzheimer's disease (AD). This identified two molecules, a pseudozoanthoxanthin (1) and a bromo-pyrrole alkaloid (2), which were predicted by a computational approach to possess interesting multitarget profiles on AD target proteins. Biochemical assays experimentally confirmed their biological activities. The two compounds inhibit acetylcholinesterase, butyrylcholinesterase, and beta-secretase enzymes in high-to submicromolar range. They are also able to prevent and revert beta-amyloid (A beta) aggregation of both A beta(1-40) and A beta(1-42) peptides, with 1 being more active than 2. Preliminary in vivo studies suggest that compound 1 is able to restore cholinergic corticohippocampal functional connectivity.

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.

Two additional new members of the onchidione family, 16-epi-onchidione (1) and 4-epi-onchidione (2), co-occurring with six previously reported bis-gamma-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 K-alpha radiation (lambda = 0.71073 angstrom) 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. (C) 2018 Elsevier Ltd. All rights reserved.

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 furanosesquiter- penes 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.

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.

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 mu M.

Two new renieramycin-type bistetrahydroisoquinolinequinone alkaloids, fennebricins A (1) and B (5), and one new isoquinolinequinone alkaloid, N-formyl-1,2-dihydrorenierol (7), were isolated from the skin of the South China Sea nudibranch Jorunna funebris and its possible sponge-prey Xestospongia sp., together with eight known metabolites, including three bistetrahydroisoquinolinequinones (2-4) and five isoquinolinequinones (8-12). Their structures were elucidated by analysis of spectroscopic data including 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry (HRESIMS) and by comparison with data for related known compounds. All the metabolites except for 7 occurred simultaneously in the two animals, supporting recent ecological studies that the nudibranch J. funebris preys on the sponge of the genus Xestospongia. © 2014 Elsevier B.V.

Alcyonacean soft corals lack physical or skeletal defenses and their nematocyst system is weak, leading to the conclusion that soft corals mainly rely on chemistry for protection from predators and microbes. Defensive chemicals of primary and secondary metabolic origin are exuded in the mucus surface layer, explaining the general lack of heavy fouling and predation in corals. In Antarctic ecosystems, where generalist predation is intense and mainly driven by invertebrate consumers, the genus Alcyonium is represented by eight species. Our goal was to investigate the understudied chemical ecology of Antarctic Alcyonium soft corals. We obtained six samples belonging to five species: A. antarcticum, A. grandis, A. haddoni, A. paucilobulatum, and A. roseum, and assessed the lipid-soluble fractions for the presence of defensive agents in these specimens. Ethyl ether extracts were tested in feeding bioassays with the sea star Odontaster validus and the amphipod Cheirimedon femoratus as putative sympatric predators. Repellent activities were observed towards both consumers in all but one of the samples assessed. Moreover, three of the extracts caused inhibition to a sympatric marine bacterium. The ether extracts afforded characteristic illudalane sesquiterpenoids in two of the samples, as well as particular wax esters subfractions in all the colonies analyzed. Both kinds of metabolites displayed significant deterrent activities demonstrating their likely defensive role. These results suggest that lipophilic chemicals are a first line protection strategy in Antarctic Alcyonium soft corals against predation and bacterial fouling.

Phidianidine B (1), a natural 1,2,4-oxadiazole linking both an indole system and an aminoalkyl guanidine group that has been recently reported from a marine mollusk, has been synthesized in seven steps (14% total yield). The synthetic procedure, which is based on the coupling of 3-indolacetic acid methyl ester and the amino-alkyl hydroxy guanidine intermediate 2, opportunely prepared, is of general application and allows the synthesis of analogues with either different alkyl chain length or substitution on the indole ring.

Chemical analysis of the secondary metabolites of Posidonia oceanica rhizomes led to the identification of several compounds. In particular, two neolignans, co-occurring with related metabolites previously described from the plant kingdom, have been isolated and characterised by spectroscopic methods. To the best of our knowledge, this is the first report of neolignans from a marine phanerogam.

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., SCOPUS: ar.j, info:eu-repo/semantics/published

The chemical analysis of the ascidian Aplidium fuegiense resulted in the isolation of three novel meroterpenoids 2–4, structurally related to the main co-occurring known rossinone B (1). The structures of the new compounds were determined by interpretation of spectroscopic data. Compounds 1–4 were found to be selectively localized in the viscera of the ascidian.

The absolute configurations of onchidione (1), previously reported from the marine pulmonate Onchidium sp., and the related alcohols onchidiol (2) and 4-epi-onchidiol (3), first described as methanolysis products of 1, were assigned by X-ray diffraction analysis and solid-state time-dependent density functional theory electronic circular dichroism. Alcohol 3 was incorrectly reported as the C-16 epimer of 2.

Two new prenylgermacrane-type diterpenoids, lobophytumins A and B (1 and 2), two new prenyleudesmane-type diterpenoids, lobophytumins C and D (3 and 4), and two new spatane-type diterpenoids, lobophytumins E and F (5 and 6), were isolated from the Hainan soft coral Lobophytum crista turn Tixier-Durivault. Their structures, including relative configuration, were elucidated by detailed analysis of spectroscopic data and by comparison with related known compounds. In addition, the absolute configuration of lobophytumin C (3) was tentatively assigned by comparing its specific rotation with that of the closely related model compound (-)-beta-selinene (8). On the basis of biogenetic considerations, the absolute configurations of lobophytumins A, B, and D F were also tentatively suggested. This is the first report of spatane-type diterpenoids from a soft coral source. The present work supports Faulkner's proposal of prenylgermacrene as the precursor of many diterpenes. In a bioassay, lobophytumins C and D (3 and 4) showed weak in vitro cytotoxicities against the tumor cell lines A-549 and HCT-116.