Quorum sensing inhibitors from Leucetta chagosensis Dendy, 1863.

UNLABELLED: Sponges are a rich source for investigation of bioactive small molecules. They have been mostly investigated for the search of new pharmacological models or therapeutic agents for the treatment of human diseases. Micro-organisms can also represent a virulent pathogen for marine invertebrates such as sponges, which need to protect themselves against these microbes. Sponges' self defence mechanisms involving dialogue molecules thus represent a pertinent research track for potent anti-infective and anti-biofilm activities such as quorum sensing inhibitors (QSIs). The investigation of the QSI crude extract of Leucetta chagosensis Dendy, 1863 led to the isolation of three new alkaloids, isonaamine D, di-isonaamidine A and leucettamine D, along with the known isonaamine A and isonaamidine A. Isonaamidine A and isonaamine D were identified as inhibitors of the three quorum sensing pathways of Vibrio harveyi (CAI-1, AI-2 and harveyi auto inducer), but isonaamidine A displayed the strongest activity on AI-2 biosensor. Both compounds are new examples of natural QSIs of V. harveyi. These results outline the importance of these secondary metabolites for their producing organisms themselves in their natural environment, as well as the potential of the marine resource for aquaculture needs. SIGNIFICANCE AND IMPACT OF THE STUDY: A new type of quorum sensing inhibitors was isolated from the sponge Leucetta chagosensis. One of them inhibits strongly the AI-2 channel of Vibrio harveyi, a marine pathogen of special importance in aquaculture. The activity of five different related compounds, including three new natural products discovered there, was investigated leading to structure-activity relationships which are useful for the design of new quorum sensing inhibitors to control marine infectious pathogens.

The occurrence of the human glycoconjugate C(2)-alpha-D-mannosylpyranosyl-L-tryptophan in marine ascidians.

[structure: see text] The C-glycoconjugate C(2)-alpha-D-mannosylpyranosyl-L-tryptophan (1), a metabolite known to be generated in humans through a novel posttranslational process, has been isolated from marine ascidians Leptoclinides dubius and Pharyngodictyon cauliflos and its N(alpha)-methyl derivative (2) from Ritterella rete.

Effects of bistramide A on a non-small-cell bronchial carcinoma line.

The antiproliferative effects of bistramide A, a nitrogenous dilactam polyether from Lissoclinum bistratum Sluiter (Urochordata), were studied at the level of the cell cycle in asynchronous cells of the NSCLCN6-L16 line. Bistramide A has a dual mechanism that induces blockade in the G1 phase (compatible with differentiation properties reported elsewhere) and causes polyploidy that is suggestive of inaptitude for cytokinesis. These effects confirm the results of cytomorphology studies in electron microscopy.

Alterations of transmembrane currents in frog atrial heart muscle induced by photoexcited gymnochrome A purified from the crinoid, Gymnochrinus richeri.

The effects of gymnochrome A were tested on the electrical activity of the frog atrial heart muscle. Gymnochrome A (1-5 microM) did not alter the resting potential. Gymnochrome A (5 microM) slowed the initial depolarizing phase of the spontaneously beating action potential. Under voltage-clamp conditions gymnochrome A (5 microM) did not affect the electrical constant of the membrane and the kinetic parameters of the peak Na+ current (INa) recorded in the Ringer solution containing tetraethylammonium (2 mM) and Cd2+ (1 mM) but shifted the membrane potential at which the current both activated and reached its maximal value toward more negative membrane potentials. It did not alter the reversal potential for INa, indicating that the selectivity of the Na+ channels had not changed. These observations suggest that gymnochrome A binds to the membrane and shifts the activation of INa on the voltage axis by modifying the free negative fixed charges present at the membrane surface rather than by occupying a specific site on the Na+ channel. Photoexcited gymnochrome A transiently triggered an early outward current which lengthened the time-to-peak of INa and decreased its amplitude. In addition, photoexcited gymnochrome A blocked the background K+ current. This is, to our knowledge, the first time that such effects are reported on the cardiac muscle. These observations suggest that the photoexcitation of gymnochrome produces physico-chemical effects which lead to intracellular changes. Further experiments are required to determine their nature.

The in vivo anti-plasmodial activity of haliclonacyclamine A, an alkaloid from the marine sponge, Haliclona sp.

The compound haliclonacyclamine A was isolated from the Haliclona sponge at Solomon Islands. It acts as a powerful in vitro and in vivo anti-plasmodial agent against the chloroquine-resistant Plasmodium falciparum strain FCB1and Plasmodium vinckei petteri-infected mice, respectively.

In vitro antiviral activity on dengue virus of marine natural products.

Metabolites isolated from marine invertebrates, callipeltin A, crambescidin, ptilomycalin A, celeromycalin, gymnochrome B, gymnochrome D and isogymnochrome D previously shown bioactive on either herpes simplex virus 1 or human immunodeficiency virus, were tested on a new in vitro bioassay using the dengue virus 1. Only gymnochrome D and isogymnochrome D isolated from the living fossil crinoid Gymnocrinus richeri are highly potent dengue antiviral agents.

Brominated beta-carbolines from the marine tunicate Eudistoma album.

Chemical investigation of the cytotoxic EtOH extract of the marine tunicate Eudistoma album led to the isolation of three brominated beta-carbolines which were characterized by their spectral data. Two of them, eudistomin E, which is already known for its potent antiviral activity, and the novel compound eudistalbin A [1], were shown to possess cytotoxic activity (ED50 less than 5.0 ng and 3.2 micrograms/ml respectively) in vitro against the growth of KB human buccal carcinoma cells. The third compound, eudistalbin B [2], is a new inactive natural product.

Brominated indole alkaloids from the marine tunicate Pseudodistoma arborescens.

Chemical investigation of the cytotoxic CH2Cl2-soluble extract of the marine tunicate Pseudodistoma arborescens led to the isolation of four brominated indole alkaloids, arborescidines A [1], B [2], C [3], and D [4], which were characterized by their spectral data, especially 2D nmr. Only arborescidine D [4] showed moderate activity (IC50 3 micrograms/ml) in vitro against the growth of KB human buccal carbinoma cells.

Two new alkaloids from Xestospongia sp., a New Caledonian sponge.

Five alkaloids have been isolated from a New Caledonian sponge Xestospongia sp. These include three known xestospongin derivatives, the new demethylxestospongin B (1) and a tetrahydrocarboline derivative 5. The structures of the new compounds 1 and 5 have been established by nmr studies and comparison with previously described products.

(+/-)-Gelliusines A and B, two diastereomeric brominated tris-indole alkaloids from a deep water new caledonian marine sponge (Gellius or Orina sp.).

Two new diastereomeric brominated tris-indole alkaloids occurring as enantiomeric pairs, (+/-)-gelliusines A [1] and B [2], have been isolated from a deep water New Caledonian sponge (Gellius or Orina sp.), whose crude extract exhibited cytotoxicity against KB cells. Their structures were elucidated by spectroscopic methods including one- and two-dimensional nmr spectroscopy. The major compound, (+/-) gelliusine A [1], which showed very weak cytotoxicity, proved to be active at the serotonin receptor.

A novel cytotoxic macrolide, superstolide B, related to superstolide A, from the New Caledonian marine sponge Neosiphonia superstes.

The structure of a new cytotoxic macrolide, superstolide B [1], isolated from the deep water sponge Neosiphonia superstes, collected off New Caledonia, was elucidated mainly on the basis of nmr data. Compound 1 is closely related to superstolide A [2], a major cytotoxic component isolated from that organism, but lacks the 25-hydroxyl group found in 2 and has a C-24 (C-25)-double bond.

New isomalabaricane derivatives from a new species of Jaspis sponge collected at the Vanuatu islands.

Six new cytotoxic isomalabaricane-type triterpenoids and nortriterpenoids with a 3alpha-acetoxy group were isolated, along with the known globostellatic acids B (1) and C (2), from the marine sponge Jaspis sp. collected at Vanuatu Island. The structures were determined by 2D NMR data and by comparison with spectral data of known related compounds.

New jaspamide derivatives from the marine sponge Jaspis splendans collected in Vanuatu.

Two new jaspamide derivatives (1 and 2) along with jaspamide have been isolated from the marine sponge Jaspis splendans collected in Vanuatu. Their chemical structures were determined from 1D and 2D NMR studies and MS data. These two compounds inhibited the in vitro growth of the NSCLC-N6 human tumor cell lines with IC50 values in the microg/mL range.

Effects in vitro of two marine substances, chlorolissoclimide and dichlorolissoclimide, on a non-small-cell bronchopulmonary carcinoma line (NSCLC-N6).

The antiproliferative activity of two nitrogenous labdane cytotoxic substances from Lissoclinum voeltzkowi Michaelson (Urochordata), dichlorolissoclimide (P2) and chlorolissoclimide (P1), was studied in vitro on a continuous human non-small-cell bronchopulmonary carcinoma line (NSCLC-N6) at the cell cycle level. This antiproliferative effect resulted from a blockade of G1 phase cells. Mortality occurred, regardless of the degree of cell ploidy, with cell transition to an out-of-cycle situation characteristic of a G1D terminal maturation state.

Halipeptins A and B: two novel potent anti-inflammatory cyclic depsipeptides from the Vanuatu marine sponge Haliclona species.

Two new metabolites, named halipeptins A and B, have been isolated from the marine sponge Haliclona sp. Their structures were determined by extensive use of one- and two-dimensional NMR experiments, mass spectrometry, and UV and IR spectroscopy. Halipeptin A is a novel 17-membered cyclic depsipeptide, consisting of five residues including two alanines (with L stereochemistry) and three new residues that appear to be previously undescribed from natural sources: 1,2-oxazetidine-4-methyl-4-carboxylic acid, 3-hydroxy-2,2,4-trimethyl-7-methoxydecanoic acid (HTMMD), and N-methyl-delta-hydroxyisoleucine. The HTMMD residue is substituted with 3-hydroxy-2,2,4-trimethyl-7-hydroxydecanoic acid in halipeptin B. Halipeptin A was found to possess very potent anti-inflammatory activity in vivo, causing about 60% inhibition of edema in mice at the dose of 300 microg/kg (i.p.).

Coscinosulfate, a CDC25 phosphatase inhibitor from the sponge Coscinoderma mathewsi.

The dual specificity CDC25 phosphatases dephosphorylate two inhibitory phospho-amino acids of cyclin-dependent kinases, a major family of cell cycle regulators. CDC25 inhibitors constitute new anti-mitotic agents with potential anticancer activity. While screening through a collection of natural products derived from marine organisms for CDC25A inhibitors, we purified and identified coscinosulfate 1, a sesquiterpene sulfate from the New Caledonian sponge Coscinoderma matthewsi, along with 4. The purified compound 1 displayed significant inhibitory activity towards CDC25A (IC(50): 3 microM).

Makaluvamine P, a new cytotoxic pyrroloiminoquinone from Zyzzya cf. fuliginosa.

A new pyrroloiminoquinone alkaloid (1) belonging to the makaluvamine family has been isolated from the sponge Zyzzya cf. fuliginosa collected in the waters off the Vanuatu Islands. The compound, designated makulavamine P, was characterized on the basis of its spectral data and displayed cytoxicity in the microM range on KB cells and antioxidant activity.

A new cycloamphilectene metabolite from the Vanuatu sponge Axinella sp.

A new diterpene, N-formyl-7-amino-11-cycloamphilectene (1), was isolated from the apolar extract of the Vanuatu sponge Axinella sp. The structure and relative stereochemistry were established by spectroscopic and single-crystal X-ray studies.

New sesquiterpene derivatives from the sponge Dysidea species with a selective inhibitor profile against human phospholipase A2 and other leukocyte functions.

Two new sesquiterpene cyclopentenones, dysidenones A and B (2, 3), and a new sesquiterpene aminoquinone, dysidine (4), all containing the same rearranged drimane skeleton, have been isolated from a Dysidea sp. sponge, along with bolinaquinone (1). The structures were established from 2D NMR data. Bolinaquinone (1), dysidine (4), and a 1:1 mixture of dysidenones A and B (2, 3) significantly inhibited human synovial phospholipase A2 (PLA2) at 10 microM. Compound 4, which shows an IC50 value of 2.0 microM, exerts a higher potency and selectivity toward this enzyme than the reference inhibitor manoalide. In addition, all of these compounds modulated at 10 microM other human leukocyte functions such as the degranulation process measured as elastase release and the superoxide production measured by chemiluminescence.

Neosiphoniamolide A, a novel cyclodepsipeptide, with antifungal activity from the marine sponge Neosiphonia superstes.

A novel cyclodepsipeptide, neosiphoniamolide A [1], has been isolated from the sponge Neosiphonia superstes. The structure of 1, which contains a 12-carbon hydroxy acid, glycine, valine, and a halogenated tyrosine residue in an 18-membered ring, is related to jaspamide and the geodiamolides, previously isolated from sponges. The structure was solved by spectroscopic analysis.