New bisabolane-type phenolic sesquiterpenoids from the marine sponge Plakortis simplex.

Six new bisabolane-type phenolic sesquiterpenoids, including plakordiols A-D (1-4), (7R, 10R)-hydroxycurcudiol (5) and (7R, 10S)-hydroxycurcudiol (6) were isolated from the marine sponge Plakortis simplex collected from the South China Sea. Their structures were determined based on extensive analysis of spectroscopic data. Their configurations were assigned by coupling constant analysis, NOESY correlations, and the modified Mosher's method. Furthermore, their cytotoxic and antibacterial activities were evaluated.

Metabolomic fingerprinting of Brazilian marine sponges: a case study of Plakinidae species from Fernando de Noronha Archipelago.

Marine sponges from the Plakinidae family are well known for hosting cytotoxic secondary metabolites and the Brazilian Atlantic coast and its oceanic islands have been considered as a hotspot for the discovery of new Plakinidae species. Herein, we report the chemical profile among cytotoxic extracts obtained from four species of Plakinidae, collected in Fernando de Noronha Archipelago (PE, Northeastern Brazil). Crude organic extracts of Plakinastrella microspiculifera, Plakortis angulospiculatus, Plakortis insularis, and Plakortis petrupaulensis showed strong antiproliferative effects against two different cancer cell lines (HCT-116: 86.7-100%; MCF-7: 74.9-89.5%) at 50 µg/mL, by the MTT assay. However, at a lower concentration (5 µg/mL), high variability in inhibition of cell growth was observed (HCT-116: 17.3-68.7%; MCF-7: 0.00-55.5%), even within two samples of Plakortis insularis which were collected in the west and east sides of the Archipelago. To discriminate the chemical profile, the samples were investigated by UHPLC-HRMS under positive ionization mode. The produced data was uploaded to the Global Natural Products Social Molecular Networking and organized based on spectral similarities for purposes of comparison and annotation. Compounds such as dipeptides, nucleosides and derivatives, polyketides, and thiazine alkaloids were annotated and metabolomic differences were perceived among the species. To the best of our knowledge, this is the first assessment for cytotoxic activity and chemical profiling for Plakinastrella microspiculifera, Plakortis insularis and Plakortis petrupaulensis, revealing other biotechnologically relevant members of the Plakinidae family.

Four new polyhydroxylated steroids from the South Sea sponge Plakortis sp.

Four new polyhydroxylated steroids plaksterols A-D (1-4), together with two known related steroids ergost-7,9(11),22-trien-3ß,5α,6α-triol (5) and ergosta-6ß-methoxy-7,22-diene-3ß,5α-diol (6), were isolated from methanol extract of the South China Sea marine sponge Plakortis sp. Their structures were identified by spectroscopic analysis, including NMR, MS, and IR. The cytotoxicity of the polyhydroxylated steroids were evaluated, and compound 6 showed moderate inhibitory activities against K562, HL-60 and BEL-7402 cells.

Exploring the Sponge Consortium Plakortis symbiotica-Xestospongia deweerdtae as a Potential Source of Antimicrobial Compounds and Probing the Pharmacophore for Antituberculosis Activity of Smenothiazole A by Diverted Total Synthesis.

Fractionation of the bioactive CHCl3-MeOH (1:1) extracts obtained from two collections of the sponge consortium Plakortis symbiotica-Xestospongia deweerdtae from Puerto Rico provided two new plakinidone analogues, designated as plakinidone B (2) and plakinidone C (3), as well as the known plakinidone (1), plakortolide F (4), and smenothiazole A (5). The structures of 1-5 were characterized on the basis of 1D and 2D NMR spectroscopic, IR, UV, and HRMS analysis. The absolute configurations of plakinidones 2 and 3 were established through chemical correlation methods, VCD/ECD experiments, and spectroscopic data comparisons. When assayed in vitro against Mycobacterium tuberculosis H37Rv, none of the plakinidones 1-3 displayed significant activity, whereas smenothiazole A (5) was the most active compound, exhibiting an MIC value of 4.1 µg/mL. Synthesis and subsequent biological screening of 8, a dechlorinated version of smenothiazole A, revealed that the chlorine atom in 5 is indispensable for anti-TB activity.

Chemistry and Selective Tumor Cell Growth Inhibitory Activity of Polyketides from the South China Sea Sponge Plakortis sp.

Simplextone E (1), a new metabolite of polyketide origin, was isolated with eight known analogues (2-9) from the South China Sea sponge Plakortis sp. The relative configuration of the new compound was elucidated by a detailed analysis of the spectroscopic data and quantum mechanical calculation of NMR chemical shifts, aided by the newly reported DP4+ approach. Its absolute configuration was determined by the TDDFT/ECD calculation. Simplextone E (1) is proven to be one of the isomers of simplextone D. The absolute configuration at C-8 in alkyl chain of plakortone Q (2) was also assigned based on the NMR calculation. In the preliminary in vitro bioassay, compounds 6 and 7 showed a selective growth inhibitory activity against HCT-116 human colon cancer cells with IC50 values of 8.3 ± 2.4 and 8.4 ± 2.3 µM, corresponding to that of the positive control, adriamycin (IC50 4.1 µM). The two compounds also showed selective activities towards MCF-7 human breast cancer and K562 human erythroleukemia cells while compound 3 only displayed weak activity against K562 cells.

Sponge symbioses between Xestospongia deweerdtae and Plakortis spp. are not motivated by shared chemical defense against predators.

The recently described epizoic sponge-sponge symbioses between Xestospongia deweerdtae and two species of Plakortis present an unusual series of sponge interactions. Sponges from the genus Plakortis are fierce allelopathic competitors, rich in cytotoxic secondary metabolites, and yet X. deweerdtae flourishes as an epizoic encrustation on Plakortis deweerdtaephila and Plakortis symbiotica. Our objective in this study was to evaluate the hypothesis that X. deweerdtae grows epizoic to these two species of Plakortis due to a shared chemical defense against predators. We collected free-living individuals of X. deweerdtae and symbiotic pairs from a wide geographical range to generate crude organic extracts and a series of polarity fractions from sponge extract. We tested the deterrency of these extracts against three common coral reef predators: the bluehead wrasse, Thalassoma bifasciatum, the Caribbean sharpnose puffer, Canthigaster rostrata, and the white spotwrist hermit crab, Pagurus criniticornis. While the chemical defenses of P. deweerdtaephila and P. symbiotica are more potent than those of X. deweerdtae, all of the sponge species we tested significantly deterred feeding in all three generalist predators. The free-living form of X. deweerdtae is mostly defended across the region, with a few exceptions. The associated form of X. deweerdtae is always defended, and both species of Plakortis are very strongly defended, with puffers refusing to consume extract-treated pellets until the extract was diluted to 1/256× concentration. Using diode-array high performance liquid chromatography (HPLC) coupled with high-resolution mass spectrometry (LC-MS/IT-TOF), we found two secondary metabolites from P. deweerdtaephila, probably the cyclic endoperoxides plakinic acid I and plakinic acid K, in low concentrations in the associated-but not the free-living-form of X. deweerdtae, suggesting a possible translocation of defensive chemicals from the basibiont to the epibiont. Comparing the immense deterrency of Plakortis spp. extracts to the extracts of X. deweerdtae gives the impression that there may be some sharing of chemical defenses: one partner in the symbiosis is clearly more defended than the other and a small amount of its defensive chemistry may translocate to the partner. However, X. deweerdtae effectively deters predators with its own defensive chemistry. Multiple lines of evidence provide no support for the shared chemical defense hypothesis. Given the diversity of other potential food resources available to predators on coral reefs, it is improbable that the evolution of these specialized sponge-sponge symbioses has been driven by predation pressure.

Plakofuranolactone as a Quorum Quenching Agent from the Indonesian Sponge Plakortis cf. lita.

There is an urgent need for novel strategies to fight drug resistance and multi-drug resistance. As an alternative to the classic antibiotic therapy, attenuation of the bacteria virulence affecting their Quorum sensing (QS) system is a promising approach. Quorum sensing (QS) is a genetic regulation system that allows bacteria to communicate with each other and coordinate group behaviors. A new γ-lactone that is capable of inhibiting the LasI/R QS system, plakofuranolactone (1), was discovered in the extract of the marine sponge Plakortis cf. lita, and its structure, including absolute configuration, was determined by NMR spectroscopy, MS spectrometry, and quantum-mechanical prediction of optical rotation. The quorum quenching activity of plakofuranolactone was evaluated using reporter gene assays for long- and short-chain signals (E. coli pSB1075, E. coli pSB401, and C. violeaceum CV026) and was confirmed by measuring the total protease activity (a virulence factor which is under control of the LasI/R system) of the wild-type P. aeruginosa PAO1. Further research will be pursued to assess the potential of plakofuranolactone as a new antivirulence lead compound and a chemical tool to increase the knowledge in this field.

Cytotoxicity of Endoperoxides from the Caribbean Sponge Plakortis halichondrioides towards Sensitive and Multidrug-Resistant Leukemia Cells: Acids vs. Esters Activity Evaluation.

The 6-epimer of the plakortide H acid (1), along with the endoperoxides plakortide E (2), plakortin (3), and dihydroplakortin (4) have been isolated from a sample of the Caribbean sponge Plakortis halichondrioides. To perform a comparative study on the cytotoxicity towards the drug-sensitive leukemia CCRF-CEM cell line and its multi-drug resistant subline CEM/ADR5000, the acid of plakortin, namely plakortic acid (5), as well as the esters plakortide E methyl ester (6) and 6-epi-plakortide H (7) were synthesized by hydrolysis and Steglich esterification, respectively. The data obtained showed that the acids (1, 2, 5) exhibited potent cytotoxicity towards both cell lines, whereas the esters showed no activity (6, 7) or weaker activity (3, 4) compared to their corresponding acids. Plakortic acid (5) was the most promising derivative with half maximal inhibitory concentration (IC50) values of ca. 0.20 µM for both cell lines.

Plakortinic Acids A and B: Cytotoxic Cycloperoxides with a Bicyclo[4.2.0]octene Unit from Sponges of the Genera Plakortis and Xestospongia.

Plakortinic acids A (2) and B (3), two polyketide endoperoxides with a bicyclo[4.2.0]octene unit, were isolated as minor constituents from the sponge-sponge symbiotic association Plakortis halichondrioides-Xestospongia deweerdtae, along with known epiplakinic acid F (1). The structures of the mixture of two inseparable compounds were determined by spectroscopic analysis. Screening for cytotoxic activity of the mixture against two human tumor cell lines revealed that these compounds are very active at sub-micromolar concentration.

Computational strategies to explore antimalarial thiazine alkaloid lead compounds based on an Australian marine sponge Plakortis Lita.

In this work, an attempt was made to propose new leads based on the natural scaffold Thiaplakortone-A active against malaria. The 2D QSAR studies suggested that three descriptors correlate with the anti-malarial activity with an R2 value of 0.814. Robustness, reliability, and predictive power of the model were tested by internal validation, external validation, Y-scrambling, and applicability domain analysis. HQSAR studies were carried out as an additional tool to find the sub-structural fingerprints. The CoMFA and CoMSIA models gave Q2 values of 0.813 and 0.647, and [Formula: see text] values of 0.994 and 0.984, respectively. Using the 2D-QSAR equation, the activity values of the seven modified compounds were calculated and it was found that three molecules showed good anti-malarial activity. Molecular docking of the 42 Thiaplakortone-A derivatives with Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was carried out to find out protein-ligand interactions. Data mining of the bioassay data-set AID: 504850 using the classifier based on Random Forest of Weka suggested that all of the eight molecules selected and three out of the seven virtual molecules were anti-malarial active. Both the virtual molecules and drug molecules were docked with CYP3A4, indicating that the virtual molecules could metabolize easily. Toxicity studies using Osiris shows that three molecules showed no toxic characters.

Total Synthesis of (±)-Gracilioether F.

Total synthesis of (±)-gracilioether F was achieved via a pivotal reductive cleavage of 1,2-dioxane from allenic ester in 11 steps. The key 1,2-dioxane species, derived from singlet oxygen and a diene, could be used as a common precursor for a stereocontrolled formation of the crucial 1,4-diol through a reductive cleavage.

Manadodioxans A-E: polyketide endoperoxides from the marine sponge Plakortis bergquistae.

Five new polyketide endoperoxides, manadodioxans A-E, were isolated from the marine sponge Plakortis bergquistae. Manadodioxan E showed antimicrobial activity against Escherichia coli at 10 µg/disk, while its oxo congener, manadodioxan D, was inactive.

Endoperoxide polyketides from a Chinese Plakortis simplex: further evidence of the impact of stereochemistry on antimalarial activity of simple 1,2-dioxanes.

Chemical investigation of the organic extract obtained from the sponge Plakortis simplex collected in the South China Sea afforded five new polyketide endoperoxides (2 and 4-7), along with two known analogues (1 and 3). The stereostructures of these metabolites have been deduced on the basis of spectroscopic analysis and chemical conversion. The isolated endoperoxide derivatives have been tested for their in vitro antimalarial activity against Plasmodium falciparum strains, showing IC50 values in the low micromolar range. The structure-activity relationships were analyzed by means of a detailed computational investigation and rationalized in the light of the mechanism of action proposed for this class of simple antimalarials. The relative orientation of the atoms involved in the putative radical generation and transfer reaction was demonstrated to have a great impact on the antimalarial activity. The resulting 3D pharmacophoric model can be a useful guide to design simple and effective antimalarial lead compounds belonging to the class of 1,2-dioxanes.

New constituents from the Korean sponge Plakortis simplex.

Six new cyclic peroxides (1-6) were isolated from the Korean sponge Plakortis simplex, along with two new alkylpyridinium alkaloids (7 and 8). The structures of these compounds were completely determined by a combination of NMR analysis and chemical reactions. Compounds 1-6 exhibited cytotoxic/antifungal activities against RAW264.7 cells and Candida albicans.

Natural and semisynthetic analogues of manadoperoxide B reveal new structural requirements for trypanocidal activity.

Chemical analysis of the Indonesian sponge Plakortis cfr. lita afforded two new analogues of the potent trypanocidal agent manadoperoxide B (1), namely 12-isomanadoperoxide B (2) and manadoperoxidic acid B (3). These compounds were isolated along with a new short chain dicarboxylate monoester (4), bearing some interesting relationships with the polyketide endoperoxides found in this sponge. Some semi-synthetic analogues of manadoperoxide B (6-8) were prepared and evaluated for antitrypanosomal activity and cytotoxicity. These studies revealed crucial structure-activity relationships that should be taken into account in the design of optimized and simplified endoperoxyketal trypanocidal agents.

Cytotoxic polyketide derivatives from the South China Sea sponge Plakortis simplex.

Five new polyketides, plakortoxides A (1) and B (2), simplextones C (3) and D (4), and plakorsin D (5), together with six known analogues (6-11) were isolated from the South China Sea sponge Plakortis simplex. Their structures were identified by spectroscopic and chemical methods, including NMR, MS, and IR. Experimental and calculated ECD spectra and the modified Mosher's method were used to determine the absolute configurations. Structurally, both plakortoxides A and B feature a butenolide coupled to an epoxide moiety, while simplextones C and D consist of γ-butyrolactone and cyclopentane moieties, and plakorsin D is a furan acetic acid polyketide. The cytotoxic activities of the isolates were tested, and compounds 8, 10, and 11 showed potent cytotoxicity against both K562 and HeLa tumor cell lines with IC50 values ranging from 0.8 to 5.3 µM. Compound 3 showed significant inhibitory activity against c-Met kinase.

Manzamenone O, new trimeric fatty acid derivative from a marine sponge Plakortis sp.

A new structurally unique trimeric fatty acid derivative, manzamenone O (1), was isolated from a marine sponge Plakortis sp. Manzamenone O (1) has a novel skeleton consisting of C-C bonded octahydroindenone and dioxabicyclo[3.3.0]octane moieties and three long aliphatic chains. The structure of 1 was elucidated on the basis of spectroscopic data and conformational analysis. Manzamenone O (1) exhibited antimicrobial activity against Micrococcus luteus, Aspergillis niger, and Trichophyton mentagrophytes.

Manzamenones L-N, new dimeric fatty-acid derivatives from an Okinawan marine sponge Plakortis sp.

Three new polyketides, manzamenones L-N (1-3), have been isolated from an Okinawan marine sponge of the genus Plakortis. The structures of 1-3 were elucidated on the basis of spectroscopic data. Manzamenones L-N (1-3) were new dimeric fatty-acid derivatives consisting of a tetrahydroindenone with three carboxy groups and two hexadecanyl chains. Manzamenones M (2) and N (3) showed antimicrobial activity against several bacteria and fungi.

The plakotenins: biomimetic Diels-Alder reactions, total synthesis, structural investigations, and chemical biology.

The total synthesis of plakotenin, a cytotoxic marine natural product, using a biomimetic Diels-Alder reaction is described in detail. Two approaches were used, whereby the Diels-Alder reaction occurs at different stages of the synthesis. Homo- and nor-plakotenin, related natural products, were also prepared, as well as iso-plakotenin, a diastereoisomer of plakotenin. The syntheses prove the relative and absolute stereochemistry of the latter. The chemical biology of the plakotenins was investigated on selected compounds.

Plakortolide stereochemistry revisited: the checkered history of plakortolides e and I.

The relative configuration of the plakortolide metabolite (4) isolated from a Madagascan Plakortis sp. and named (+)-plakortolide I is revised following reassignment of the ¹³C signals for C-7 and C-16, thereby establishing that the metabolite isolated was likely (+)-plakortolide E (3). We propose that the name "plakortolide I" should be retained for the plakortolide metabolite 5 first isolated by the Faulkner group; its enantiomer 4 can then be named ent-plakortolide I in line with the description of Barnych and Vatèle. The spectroscopic data for MPA esters prepared from synthetic samples of seco derivatives of plakortolide E (3) and ent-plakortolide I (4) were compared with those of MPA esters of seco derivatives from naturally isolated plakortolides L (1) and K (2) and of seco-plakortolide E (6a). Likewise, the spectroscopic data for MTPA esters derived from 3 and 4 were compared with data for the MTPA esters derived from 5. These various comparisons established that the sign of the specific rotation associated with the natural isolates is an unreliable indicator of absolute configuration and verify that the absolute configurations of plakortolides L (1), K (2), E (3), and I (5) are (3S, 4S, 6S), (3R, 4R, 6S), (3R, 4R, 6R), and (3S, 4S, 6R), respectively.