Arenarialins A-F, Anti-inflammatory Meroterpenoids with Rearranged Skeletons from the Marine Sponge Dysidea arenaria.

Six new sesquiterpene quinone/hydroquinone meroterpenoids, arenarialins A-F (1-6), were isolated from the marine sponge Dysidea arenaria collected from the South China Sea. Their chemical structures and absolute configurations were determined by HRMS and NMR data analyses coupled with DP4+ and ECD calculations. Arenarialin A (1) features an unprecedented tetracyclic 6/6/5/6 carbon skeleton, whereas arenarialins B-D (2-4) possess two rare secomeroterpene scaffolds. Arenarialins A-F showed inhibitory activity on the production of inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages with arenarialin D regulating the NF-κB/MAPK signaling pathway.

Dysideanones F-G and dysiherbols D-E, unusual sesquiterpene quinones with rearranged skeletons from the marine sponge Dysidea avara.

Four new sesquiterpene quinone meroterpenoids, dysideanones F-G (1-2) and dysiherbols D-E (3-4), were isolated from the marine sponge Dysidea avara collected from the South China Sea. The new structures were elucidated by extensive analysis of spectroscopic data including HR-MS and 1D and 2D NMR spectra, and their absolute configurations were assigned by single-crystal X-ray diffraction and ECD calculations. Anti-inflammatory evaluation showed that dysiherbols D-E (3-4) exhibited moderate inhibitory activity on TNF-α-induced NF-κB activation in human HEK-293T cells with IC50 values of 10.2 and 8.6 µmol·L-1, respectively.

Dysideanones F-G and dysiherbols D-E, unusual sesquiterpene quinones with rearranged skeletons from the marine sponge Dysidea avara / 中国天然药物

Four new sesquiterpene quinone meroterpenoids, dysideanones F-G (1-2) and dysiherbols D-E (3-4), were isolated from the marine sponge Dysidea avara collected from the South China Sea. The new structures were elucidated by extensive analysis of spectroscopic data including HR-MS and 1D and 2D NMR spectra, and their absolute configurations were assigned by single-crystal X-ray diffraction and ECD calculations. Anti-inflammatory evaluation showed that dysiherbols D-E (3-4) exhibited moderate inhibitory activity on TNF-α-induced NF-κB activation in human HEK-293T cells with IC50 values of 10.2 and 8.6 μmol·L-1, respectively.

New NF-κB Inhibitory Steroids from the Marine Sponge Dysidea avara Collected from the South China Sea.

Chemical investigation of the marine sponge Dysidea avara, collected from the South China Sea, yielded 13 steroids, including nine new (1-9) and four known (10-13) ones. The new structures were elucidated as (3S,14R)-3,14-dihydroxycholesta-5,8-dien-7-one (1), (22E,24R)-7α-ethoxy-5α,6α-epoxyergosta-8(14),22-dien-3ß-ol (2), 3ß-hydroxy-7α-ethoxy-5α,6α-epoxy-8(14)-cholestene (3), 3ß,5α-dihydroxy-6α-ethoxychofesta-7,9(11)-diene (4), 3ß,5α-dihydroxy-6ß-ethoxycholest-7-ene (5), (22E,24R)-24-ethoxy-3ß,5α-dihydroxy-6ß-ethoxyergosta-7,22-diene (6), (22E)-3ß,5α-dihydroxy-6ß-ethoxycholesta-7,22-diene (7), 24-ethoxy-3ß,5α-dihydroxy-6ß-ethoxycholest-7-ene (8 and 9), by extensive spectroscopic analyses, such as HR-ESI-MS, 1D and 2D NMR data. The absolute configuration of 1 was assigned by comparison the experimental ECD spectra with the calculated ones. Among the 13 metabolites, compounds 1, 4, 11, 12, and 13 showed NF-κB inhibitory activities in human HER-293 cells with IC50 values of 6.4, 18.7, 8.1, 9.6, and 7.5 µM, respectively. Preliminary structure-activity relationship analysis unveiled that the conjugated ketones or unsaturated double bonds might be the functional groups for the five active steroids.

Dysiscalarones A-E, scalarane sesterterpenoids with nitric oxide production inhibitory activity from marine sponge Dysidea granulosa.

Dysiscalarones A-E (1-5), five new scalarane-type bishomoscalarane sesterterpenoids, were isolated from marine sponge Dysidea granulosa collected from the South China Sea, together with two known ones, honulactone A (6) and phyllofolactone I (7). The new structures were determined by extensive spectroscopic analysis including HR-ESI-MS and 1D and 2D NMR data, and their absolute configurations were assigned by single crystal X-ray diffraction analyses. The inhibitory activity of all the seven isolates on the production of nitric oxide (NO) stimulated by lipopolysaccharide (LPS) in mouse RAW 264.7 macrophages was evaluated. Of these metabolites, dysiscalarones A-B (1-2), honulactone A (6), and phyllofolactone I (7) showed inhibitory activities with respective IC50 values of 16.4, 18.5, 2.6, and 3.7 µM, which suggested that the γ-methylated α,ß-unsaturated γ-lactone might be the functional group. In addition, all the seven metabolites showed no significant cytotoxicity against lung cancer PC9 cell line at the concentration of 20 µM.

Cytotoxic sesquiterpenoid quinones from South China Sea sponge Dysidea sp.

A new sesquiterpene, (+)-19-methylaminoavarone (1), together with six known compounds (2-7), were isolated from the Xisha Islands marine sponge Dysidea sp. The structures were elucidated based on their spectroscopic data. We revised the carbon spectrum data of the compound 2. The absolute configurations of compounds 1 and 2 were further confirmed by electronic circular dichroism (ECD) analysis. Compounds 1-3 and 5-7 showed potent cytotoxic activity against several human cancer cell lines.

Structure-Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer.

Synthetic analogues of the marine natural product sintokamides have been prepared in order to investigate the structure-activity relationships for the androgen receptor N-terminal domain (AR NTD) antagonist activity of the sintokamide scaffold. An in vitro LNCaP cell-based transcriptional activity assay with an androgen-driven luciferase (Luc) reporter was used to monitor the potency of analogues. The data have shown that the chlorine atoms on the leucine side chains are essential for potent activity. Analogues missing the nonchlorinated methyl groups of the leucine side chains (C-1 and C-17) are just as active and in some cases more active than the natural products. Analogues with the natural R configuration at C-10 and the unnatural R configuration at C-4 are most potent. Replacing the natural propionamide N-terminus cap with the more sterically hindered pivaloylamide N-terminus cap leads to enhanced potency. The tetramic acid fragment and the methyl ether on the tetramic acid fragment are essential for activity. The SAR optimized analogue 76 is more selective, easier to synthesize, more potent, and presumed to be more resistant to proteolysis than the natural sintokamides.

Dysidealactams and Dysidealactones: Sesquiterpene Glycinyl-Lactams, Imides, and Lactones from a Dysidea sp. Marine Sponge Collected in Southern Australia.

A GNPS molecular networking approach mapped a library of 960 southern Australian marine sponges and prioritized Dysidea sp. (CMB-01171) for chemical investigation. Although the published natural products literature on Australian Dysidea sponges extends back over half a century and suffers from the perception of being near exhausted, fractionation of Dysidea sp. (CMB-01171) led to the discovery of a family of 10 new biosynthetically and chemically related sesquiterpenes. Detailed spectroscopic analysis guided structure elucidation identified dysidealactams A-F (1-6), dysidealactones A and B (7 and 8), and two solvolysis artifacts, 9 and 10. The dysidealactams A-D (1-4) incorporate a rare glycinyl-lactam functionality, while dysidealactam E (5) is particularly noteworthy in incorporating an unprecedented glycinyl-imide moiety. In addition to expanding knowledge of Dysidea natural products, this study demonstrates the value of applying GNPS molecular networking to map chemical diversity and prioritize the selection of marine sponge extracts for more detailed chemical analysis.

Cytotoxicity Activity and Druggability Studies of Sigmasterol Isolated from Marine Sponge Dysidea avara Against Oral Epithelial Cancer Cell (KB/C152) and T-Lymphocytic Leukemia Cell Line (Jurkat/ E6-1).

BACKGROUND: Marine sponge is a rich natural resource of many pharmacological compounds and various bioactive anticancer agents are derived from marine organisms like sponges. METHODS: studying the anticancer activity and Drug ability of marine sponge Dysidea avara using Cell lines oral epithelial cancer cell (KB/C152) and T-lymphocytic leukemia cell line (Jurkat/ E6-1). Marine sponge was collected from Persian Gulf. Several analytical techniques have been used to obtain and recognize stigmasterol, including column chromatography, thin layer chromatography, and gas chromatography-mass spectrometry. The PASS Prediction Activity was used to investigate the apoptosis-inducing effect of stigmasterol. The cytotoxic activity of stigmasterol was examined using yellow tetrazolium salt XTT (sodium 2, 3,-bis (2methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium) assay. The stigmasterol were docked within the protein tyrosine kinase (PTKs) (PDB code: 1t46) and epidermal growth factor receptor (EGFRK) (PDB code: 1M17). Also, the pharmacological characteristics of stigmasterol were predicted using PerADME, SwissADME, and Molinspi ration tools. Apoptosis-inducing effect of stigmasterol indicate the stigmasterol in terms of the possibility of apoptosis in cells. RESULTS: The apoptosis inducement results of known stigmasterol were determined by PASS on-line prediction. The compound exhibit potent cytotoxic properties against KB/C152 cell compared to Jurkat/ E6-1 cell. The stigmasterol showed the cytotoxicity effects on KB/C152 and HUT78 with IC50 ranges of 81.18 and 103.03 µg/ml, respectively. Molecular docking showed that, stigmasterol bound stably to the active sites of the protein tyrosine kinase (PTKs) (PDB code: 1t46) and epidermal growth factor receptor (EGFRK) (PDB code: 1M17). CONCLUSION: The compound showed desirable pharmacokinetic properties (ADME). This provided direct evidence of how a prospective anti-cancer agent can be stigmasterol. The preclinical studies paved the way for a potential new compound of anti-cancer.

Investigating the Antiparasitic Potential of the Marine Sesquiterpene Avarone, Its Reduced form Avarol, and the Novel Semisynthetic Thiazinoquinone Analogue Thiazoavarone.

The chemical analysis of the sponge Dysidea avara afforded the known sesquiterpene quinone avarone, along with its reduced form avarol. To further explore the role of the thiazinoquinone scaffold as an antiplasmodial, antileishmanial and antischistosomal agent, we converted the quinone avarone into the thiazinoquinone derivative thiazoavarone. The semisynthetic compound, as well as the natural metabolites avarone and avarol, were pharmacologically investigated in order to assess their antiparasitic properties against sexual and asexual stages of Plasmodium falciparum, larval and adult developmental stages of Schistosoma mansoni (eggs included), and also against promastigotes and amastigotes of Leishmania infantum and Leishmania tropica. Furthermore, in depth computational studies including density functional theory (DFT) calculations were performed. A toxic semiquinone radical species which can be produced starting both from quinone- and hydroquinone-based compounds could mediate the anti-parasitic effects of the tested compounds.

Bishomoscalarane Sesterterpenoids from the Sponge Dysidea granulosa Collected in the South China Sea.

Granulosane A (1), a new C27 bishomoscalarane sesterterpenoid with a rare 6/6/6/8 tetracyclic skeleton, together with eight additional new C27 bishomoscalarane sesterterpenes (2, 8-14) and five new C26 20,24-bishomo-25-norscalarane sesterterpenes (3-7), were isolated from the marine sponge Dysidea granulosa collected in the South China Sea. Their structures were elucidated by extensive spectroscopic analysis and quantum chemical calculation methods. Compound 4 showed antiproliferative activities against two cancer cell lines.

Liposomal integration method for assessing antioxidative activity of water insoluble compounds towards biologically relevant free radicals: example of avarol.

The liposomal integration method, in conjunction with electron paramagnetic resonance (EPR) spectroscopy, has been presented for the investigation of antioxidant activity of selected water-insoluble compound towards biologically relevant free radicals. This method was applied to avarol, a sesquiterpenoid hydroquinone isolated from the marine sponge Dysidea avara. The antioxidant activity of water-insoluble avarol towards •OH, O2•- and NO• radicals was attained by its incorporation into the DPPC liposomes bilayer, and towards ascorbyl radicals in the organic solvent. Avarol's activity towards •OH, O2•-, NO• and ascorbyl radicals was 86.2%, 50.9%, 23.6% and 61.8%, respectively, showing its significant radical scavenging potential.

Sponge-derived polybrominated diphenyl ethers and dibenzo-p-dioxins, irreversible inhibitors of the bacterial α-d-galactosidase.

An integrated in vitro and in silico approach was applied to evaluate the potency of hydroxylated polybrominated diphenyl ethers (OH-PBDEs) and spongiadioxins (OH-PBDDs) isolated from Dysidea sponges on the activity of the recombinant α-d-galactosidase of the GH36 family. It was revealed for the first time that all compounds rapidly and apparently irreversibly inhibited the bacterial α-d-galactosidase. The structure-activity relationship study in the series of OH-PBDEs showed that the presence of an additional hydroxyl group in 5 significantly enhanced the potency (IC50 4.26 µM); the increase of bromination in compounds from 1 to 3 increased their potency (IC50 41.8, 36.0, and 16.0 µM, respectively); the presence of a methoxy group decreased the potency (4, IC50 60.5 µM). Spongiadioxins 6, 7, and 8 (IC50 16.6, 33.1, and 28.6 µM, respectively) exhibited inhibitory action comparable to that of monohydroxylated diphenyl ethers 1-3. Docking analysis revealed that all compounds bind in a pocket close to the catalytic amino acid residues. Molecular docking detected significant compound-enzyme interactions in the binding sites of α-d-galactosidase. Superimposition of the enzyme-substrate and the enzyme-inhibitor complexes showed that their binding sites overlap.

Frondoplysins A and B, Unprecedented Terpene-Alkaloid Bioconjugates from Dysidea frondosa.

The chemical investigation of the marine sponge Dysidea frondosa discovered a pair of unprecedented bioconjugates that are composed of a meroterpene and an unusual psammaplysin alkaloid. The structures of frondoplysins A (1) and B (2) were characterized by analysis of HRMS and NMR data coupled with single-crystal X-ray diffraction. Frondoplysin A was found to be a potent inhibitor targeting protein-tyrosine phosphatase 1B (PTP1B) with an IC50 value of 0.39 µM.

Septosones A-C, in Vivo Anti-inflammatory Meroterpenoids with Rearranged Carbon Skeletons from the Marine Sponge Dysidea septosa.

Three unusual meroterpenoids, septosones A-C (1-3), were isolated from the marine sponge Dysidea septosa. The structures were determined by analysis of spectroscopic data combined with single-crystal X-ray diffraction and ECD calculations. Septosone A (1) features an unprecedented "septosane" carbon skeleton, whereas septosones B (2) and C (3) share a rare spiro[4.5]decane motif. Septosone A showed in vivo anti-inflammatory activity in CuSO4-induced transgenic fluorescent zebrafish likely through inactivation of the NF-κB signaling pathway.

Selective Cytotoxicity of α-Santonin from the Persian Gulf Sponge Dysidea Avara on Pediatric ALL B-lymphocytes via Mitochondrial Targeting

Background: Acute lymphoblastic leukemia (ALL) is one of the most dominant malignancies among children, characterized by production of immature and dysfunctional blasts which are resistant to cytotoxic chemotherapeutic agents. Therefore, research protocols are currently focusing on discovery of novel anti-cancer agents to enhance survival rates and decrease unwanted side effects. Approximately two-thirds of the planet is covered by oceans with a massive range of marine organisms of interest to scientists in pharmaceutical fields. Methods: Among marine resources, sponges are known to have beneficial effects in the treatment of numerous malignancies. One fraction of crude extracts containing α-Santonin was made from the Persian Gulf marine sponge, Dysidea avara, and investigated for anticancer effects. Results: Treatment of ALL B-lymphocytes with the Dysidea avara extract caused augmentation in ROS generation, decline in mitochondrial membrane potential, mitochondrial swelling, release of cytochrome c from mitochondria and activation of caspase-3 only in mitochondria isolated from B-ALL lymphocytes. Conclusion: In brief, our results suggest that Dysidea avara extracts may selectively induce apoptosis in malignant pediatric lymphocytes.

Dysiarenone, a Dimeric C21 Meroterpenoid with Inhibition of COX-2 Expression from the Marine Sponge Dysidea arenaria.

Dysiarenone (1), a dimeric C21 meroterpenoid featuring an unprecedented 2-oxaspiro[bicyclo[3.3.1]nonane-9,1'-cyclopentane] carbon skeleton, was isolated from the marine sponge Dysidea arenaria. The structure of 1 was determined by HRMS and NMR spectroscopic analyses coupled with ECD calculations. Dysiarenone showed inhibitory activities against COX-2 expression and the production of prostaglandin E2 with an IC50 value of 6.4 µM in LPS-stimulated RAW264.7 macrophages.

Three new sesquiterpene aminoquinones from a Vietnamese Spongia sp. and their biological activities.

Sesquiterpenoid quinones with remarkable properties, such as anti-inflammatory, antibacterial, antiviral, antitumor, antiangiogenic, and differentiation-inducing activities, have reportedly been isolated from the marine sponge genera Dysidea, Spongia, and Dactylospongia. In our continuing search for bioactive compounds from marine sponges, three new sesquiterpenoid quinones, langcoquinones D-F (1-3), were isolated from the ethyl acetate extract of Spongia sp. collected from Vietnam. Their chemical structures were elucidated on the basis of extensive spectroscopic analyses. The newly isolated compounds 1-3 were assessed for their antibacterial activities against Gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus, and Gram-negative bacteria, Klebsiella pneumoniae and Escherichia coli, as well as their cytotoxic activities against three human cancer cell lines (A549, lung cancer; MCF7, breast cancer; HeLa, cervical cancer) and a human normal cell line (WI-38 fibroblast). All compounds were inactive against the Gram-negative bacteria. Furthermore, langcoquinones E (2) and F (3) lacked antibacterial activities against the Gram-positive bacteria and cytotoxic activities against the tested cell lines. However, langcoquinone D (1) exhibited good antibacterial activities against Bacillus subtilis and Staphylococcus aureus, with MIC values of 12.5 and 25.0 µM, respectively. Furthermore, 1 exhibited significant cytotoxic activities against three human cancer cell lines (A549, lung cancer; MCF7, breast cancer; HeLa, cervical cancer) and a human normal cell line (WI-38 fibroblast).

Dysifragilone A inhibits LPS­induced RAW264.7 macrophage activation by blocking the p38 MAPK signaling pathway.

Dysifragilone A, a sesquiterpene aminoquinone based on a rearranged avarone skeleton, has been previously isolated and identified from the South China Sea sponge Dysidea fragilis. In the present study, anti­inflammatory activity and the underlying molecular mechanism of dysifragilone A were studied using the classical inflammation model of lipopolysaccharide (LPS)­activated RAW264.7 macrophage cells and an MTT assay, Griess method, ELISA and western blotting were used. The results revealed that dysifragilone A significantly reduced the release of inflammatory mediators and inflammatory cytokines in activated RAW264.7 cells, including nitric oxide (NO), prostaglandin E2,(PGE2) and interleukin­6 (IL­6). The protein expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase­2 (COX­2), and the enzymatic activity of iNOS and COX­2 were also inhibited by dysifragilone A in a dose dependent manner. Further mechanistic investigations suggested that the anti­inflammatory activity of dysifragilone A results from the suppression of p38 mitogen­activated protein kinase (MAPK) activation in LPS­activated macrophages; however, this was not associated with inhibition of the extracellular signal­regulated kinase (ERK) or c­Jun N­terminal kinase (JNK) signaling pathways. Therefore, dysifragilone A and similar compounds may be anti­inflammatories that have potential to be used in the clinic.

Dysivillosins A-D, Unusual Anti-allergic Meroterpenoids from the Marine Sponge Dysidea villosa.

Four unusual meroterpenoids, dysivillosins A-D (1-4), were isolated from an organic extract of the marine sponge Dysidea villosa collected from the South China Sea. Their planar structures were determined by 1D and 2D NMR and HRESIMS techniques, while the relative and absolute configurations were elucidated by NOESY experiments and comparison between the calculated and experimental ECD spectra. To the best of our knowledge, dysivillosins A-D are the first examples of terpene-polyketide-pyridine hybrid metabolites from the nature. Anti-allergic activity evaluation showed that compounds 1-4 potently inhibited the release of ß-hexosaminidase, a marker of degranulation, in a dose-dependent manner with IC50 values of 8.2-19.9 µM. Additionally, the four meroterpenoids could downregulate the production of lipid mediator leukotrienes B4 (LTB4) and pro-inflammatory cytokine interleukin-4 (IL-4) in the antigen-stimulated RBL-2H3 mast cells. Further biological investigations revealed that dysivillosin A (1) could suppress the phosphorylation of Syk and PLCγ1 in IgE/FcɛRI/Syk signaling pathway, which resulted in the inhibition of degranulation and the downregulation of LTB4 and IL-4 production in mast cells.