Exploring the chemical diversity of sesquiterpenes from the rarely studied south China sea soft coral Sinularia tumulosa assisted by molecular networking strategy.

Molecular networking strategy-based prioritization of the isolation of the rarely studied soft coral Sinularia tumulosa yielded 14 sesquiterpenes. These isolated constituents consisted of nine different types of carbon frameworks, namely asteriscane, humulane, capillosane, seco-asteriscane, guaiane, dumortane, cadinane, farnesane, and benzofarnesane. Among them, situmulosaols A-C (1, 3 and 4) were previously undescribed ones, whose structures with absolute configurations were established by the combination of extensive spectral data analyses, quantum mechanical-nuclear magnetic resonance and time-dependent density functional theory electronic circular dichroism calculations, the Snatzke's method, and the modified Mosher's method. Notably, situmulosaol C (4) was the second member of capillosane-type sesquiterpenes. The plausible biogenetic relationships of these skeletally different sesquiterpenes were proposed. All sesquiterpenoids were evaluated for their antibacterial, cytotoxic and anti-inflammatory effects. The bioassay results showed compound 14 exhibited significant antibacterial activities against a variety of fish and human pathogenic bacteria with MIC90 values ranging from 3.6 to 33.8 µg/mL. Moreover, moderate cytotoxic effects against HEL cells for components 13 and 14 and moderate inhibitory effect on lipopolysaccharide-induced inflammatory responses in RAW264.7 cells for substance 13 were also observed.

In Vitro Insights into the Role of 7,8-Epoxy-11-Sinulariolide Acetate Isolated from Soft Coral Sinularia siaesensis in the Potential Attenuation of Inflammation and Osteoclastogenesis.

The balance between bone-resorbing osteoclasts and bone-forming osteoblasts is essential for the process of bone remodeling. Excessive osteoclast differentiation plays a pivotal role in the pathogenesis of bone diseases such as rheumatoid arthritis and osteoporosis. In the present study, we examined whether 7,8-epoxy-11-sinulariolide acetate (Esa), a marine natural product present in soft coral Sinularia siaesensis, attenuates inflammation and osteoclastogenesis in vitro. The results indicated that Esa significantly inhibited lipopolysaccharide (LPS)-induced inflammation model of RAW264.7 cells and suppressed receptor activator for nuclear factor-κB ligand (RANKL)-triggered osteoclastogenesis. Esa significantly down-regulated the protein expression of iNOS, COX-2, and TNF-α by inhibiting the NF-κB/MAPK/PI3K pathways and reducing the release of reactive oxygen species (ROS) in RAW264.7 macrophages. Besides, Esa treatment significantly inhibited osteoclast differentiation and suppressed the expression of osteoclast-specific markers such as NFATC1, MMP-9, and CTSK proteins. These findings suggest that Esa may be a potential agent for the maintenance of bone homeostasis associated with inflammation.

Discovery of D25, a Potent and Selective MNK Inhibitor for Sepsis-Associated Acute Spleen Injury.

Mitogen-activated protein kinase-interacting protein kinases (MNKs) and phosphorylate eukaryotic initiation factor 4E (p-eIF4E) play a critical role in regulating mRNA translation and protein synthesis associated with the development of cancer, metabolism, and inflammation. This study undertakes the modification of a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine structure, leading to the discovery of 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (D25) as a potent and selective MNK inhibitor. D25 demonstrated inhibitory activity, with IC50 values of 120.6 nM for MNK1 and 134.7 nM for MNK2, showing exceptional selectivity. D25 inhibited the expression of pro-inflammation cytokines in RAW264.7 cells, such as inducible NO synthase, cyclooxygenase-2, and interleukin-6 (IL-6). In the lipopolysaccharide-induced sepsis mouse model, D25 significantly reduced p-eIF4E in spleen tissue and decreased the expression of tumor necrosis factor α, interleukin-1ß, and IL-6, and it also reduced the production of reactive oxygen species, resulting in improved organ injury caused by inflammation. This suggests that D25 may provide a potential treatment for sepsis and sepsis-associated acute spleen injury.

Genus Litophyton: A Hidden Treasure Trove of Structurally Unique and Diversely Bioactive Secondary Metabolites.

Marine soft corals are prolific sources of various natural products that have served as a wealthy reservoir of diverse chemical scaffolds with potential as new drug leads. The genus Litophyton contains almost 100 species but only a small proportion of them has been chemically investigated, which calls for more attentions from global researchers. In the current work, 175 secondary metabolites have been discussed, drawing from published data spanning almost five decades, up to July 2023. The studied species of the genus Litophyton resided in various tropical and temperate regions and encompassed a broad range of biologically active natural products including terpenes, steroids, nitrogen-containing metabolites, lipids, and other metabolites. A wide spectrum of pharmacological effects of these compounds had been evaluated, such as cytotoxic, antiviral, antibacterial, antifungal, anti-malarial, antifeedant, anti-inflammatory, molluscicidal, PTP1B inhibitory, insect growth inhibitory, and neuroprotective activities. This review aims to offer an up-to-date survey of the literature and provide a comprehensive understanding of the chemical structures, taxonomical distributions, and biological activities of the reported metabolites from the title genus whenever available.

Four New Diterpenoids from the South China Sea Soft Coral Sinularia nanolobata and DFT-Based Structure Elucidation.

Three new cembranoids (1-3) and a new casbanoid (4), along with three known analogues (5-7), have been isolated from the soft coral Sinularia nanolobata collected off Ximao Island. The structures, including the absolute configurations of new compounds, were established using extensive spectroscopic data analysis, time-dependent density functional theory/electronic circular dichroism (TDDFT-ECD) calculations, and the comparison with spectroscopic data of known compounds. In the in vitro bioassay, compounds 1 and 5 exhibited moderate cytotoxic activities against human erythroleukemia (HEL) cell lines, with IC50 values of 37.1 and 42.4 µM, respectively.

Ocellatuspyrones A‒G, new antibacterial polypropionates from the Chinese mollusk Placobranchus ocellatus.

Marine invertebrates serve as rich sources of secondary metabolites with intriguing chemical diversities and a wide spectrum of biological activities. Particularly, marine shell-less sacoglossan mollusks have attracted much attentions due to the fact that mollusks apply complex metabolites as chemical defense agents against to their predators. With the purpose of discovering bioactive secondary metabolites to develop marine-derived medicines from the South China Sea, we have conducted a chemical study on the photosynthetic mollusk Placobranchus ocellatus. As a result, seven new γ-pyrone polypropionates, namely ( ±)-ocellatuspyrone A (1), ( ±)-ocellatuspyrone B (2), and ocellatuspyrones C-G (5, 9-12), along with five known polypropionates, have been isolated and characterized from the South China Sea photosynthetic mollusk Placobranchus ocellatus. Extensive spectroscopic analysis, single crystal X-ray diffraction analysis, modified Mosher's method, ECD comparison, CD exciton chirality method, TDDFT-ECD calculation, and chemical conversion were used to determine the structures and absolute configurations of the new compounds and the stereochemistry of undefined known compounds 4, 6 and 7. All these isolated polypropionates were evaluated in bioassays for their biological activities, including antibacterial, neuroprotective effect, anti-inflammatory, PTP1B inhibitory, and antiviral activities. Compounds 7, 8 and 11 were found for the first time to show antibacterial activity against fish pathogenic bacteria Streptococcus parauberis (the main pathogen causing fish streptococcal infections and acute death) with MIC values of 35.8, 34.2, and 37.4 µg/mL, respectively, which might be potential novel antibacterial agents for the treatment of fish infectious diseases. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00179-w.

Two new compounds from the Hainan Soft Corals Sinularia tumulosa and Sinularia depressa with their anti-inflammatory or cytotoxic activities.

The detailed chemical investigations of the South China Sea soft corals Sinularia tumulosa and Sinularia depressa, yielded two new compounds, namely tumulosterol A (1) and 11'-hydroxy-α-tocopherylquinone (3), along with four related known ones (2, 5-7). Their structures were determined by extensive spectroscopic analysis and comparison with the spectral data previously reported in the literature. In bioassays, compound 1 displayed significant cytotoxic effects against H1975 and MDA-MB-231 cells with IC50 values of 6.0 and 6.3 µM, respectively. In addition, compound 3 exhibited interesting inhibitory effect on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 cells with IC50 value of 9.5 µM.

Two New Cembranoids from the Chinese Soft Coral Sarcophyton boettgeri.

Two new cembranoids, namely sarcoboettgerols D and E, together with four known related ones, have been isolated from the soft coral Sarcophyton boettgeri collected from Weizhou Island in the South China Sea. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis, quantum mechanical nuclear magnetic resonance methods, time-dependent density functional theory-electronic circular dichroism calculations, as well as comparison with the reported data in the literature. A plausible biogenetic relationship of four cembranoids was proposed. In bioassays, sarcomililatin B exhibited cytotoxic activity against H1299 cell (IC50 =35.0 µM), whereas sarcomililatin B and sarcomililatin A displayed moderate antibacterial activities (MIC 17.4-34.8 µg/mL).

Bioactivity-Driven Synthesis of the Marine Natural Product Naamidine J and Its Derivatives as Potential Tumor Immunological Agents by Inhibiting Programmed Death-Ligand 1.

The total synthesis of the marine natural product naamidine J and a rapid structure modification toward its derivatives were achieved on the basis of several rounds of structure-relationship analyses of their tumor immunological activities. These compounds were tested for programmed death-ligand 1 (PD-L1) protein expression in human colorectal adenocarcinoma RKO cells. Among them, compound 11c was found to efficiently suppress constitutive PD-L1 expression in RKO cells with low toxicity and further exerted its antitumor effect in MC38 tumor-bearing C57BL/6 mice by reducing PD-L1 expression and enhancing tumor-infiltrating T-cell immunity. This research work may provide insight for the discovery of new marine natural product-derived tumor immunological drug leads.

Antitumor Cembrane Diterpenoids from the South China Sea Soft Coral Lobophytum sp.

Two new highly functionalized cembrane diterpenoids named ximaolobophytolides A (1) and B (2) as minor components, together with seven related known compounds (3-9), have been isolated and identified from the Ximao soft coral Lobophytum sp. They were characterized by the presence of an α-methylene-γ-lactone moiety. Based on the comprehensive analyses of 1D and 2D NMR spectroscopic data, the absolute configurations of these two new compounds were elucidated by the combination of quantum mechanical (QM)-NMR and time-dependent density functional theory/electronic circular dichroism (TDDFT-ECD) calculation approaches. In the anti-tumor bioassays, compounds 3-9 showed moderate to significant inhibitory effects (IC50 values ranging from 29.66 to 0.39 µM) against the proliferations of five tumor cells HEL, A549, H1975, MDA-MB-231, and H1299. It might be worthy to point out that compounds 4, 7, and 8 exhibited better anti-tumor activities than that of the positive control Doxorubicin.

Extending the Record of Terpenes from Soft Coral Sarcophyton mililatensis.

In the present study, a new polyoxygenated cembranoid named sarcomililatol H (1) as well as six known terpenes 2-7 with different skeletons were isolated from South China Sea soft coral Sarcophyton mililatensis. Based on the comprehensive analyses of 1D and 2D NMR spectroscopic data, the structure of the new compound 1 was established. This new cembranoid was characterized by the presence of the rarely encountered tetrahydropyran ring with the ether linkage across C-2 and C-12. By applying the time-dependent density functional theory electronic circular dichroism (TDDFT ECD) approach, the absolute configuration of sarcomililatol H (1) was determined. All of the isolates were subjected to the anti-inflammatory and anti-tumor bioassays. However, none of them was active in these evaluations. Additionally, the preliminary virtual screening of inhibitory against SARS-CoV-2 by molecular docking showed that diterpene 1 could be regarded as a SARS-CoV-2 main protease (Mpro ) inhibitor (binding energy: -7.63 kcal/mol). The discovery of these terpenes has expanded the chemical diversity and complexity of terpenes from the species S. mililatensis.

Cembrane Diterpenes Possessing Nonaromatic Oxacycles from the Hainan Soft Coral Sarcophyton mililatensis.

Documents on the chemical composition of the soft coral Sarcophyton mililatensis are sparse. The present investigation of the Hainan soft coral S. mililatensis resulted in the discovery of six new cembrane diterpenes, sarcoxacyclols A-F (1-6) and four known analogs (7-10). Their structures were elucidated by extensive spectroscopic analysis along with a comparison with the data in current literature. The nonaromatic oxacycles in their structures were the rarely found tetrahydrofuran ether across C-1 and C-12 and tetrahydropyran ether across C-1 and C-11, respectively. Moreover, the absolute configuration of compound 4 was established unambiguously by X-ray diffraction analysis using Ga Kα radiation (λ = 1.34139 Å). Based on the biogenetical consideration, the absolute configurations of other five new compounds were tentatively assumed. Assessment of the bioactivity for these secondary metabolites revealed that compound 1 exhibited significant tumor necrosis factor (TNF)-α inhibitory activity (IC50 = 9.5 µmol/L), similar to the positive control dexamethasone (IC50 = 8.7 µmol/L), but no obvious cytotoxicity towards RAW264.7 cells (CC50 > 50 µmol/L). The preliminary molecular docking suggested the crucial roles of the hydroxyl and acetoxyl groups in the computational prediction of the binding mode between the diterpene and the protein.

Structurally Diverse Diterpenes from the South China Sea Soft Coral Sarcophyton trocheliophorum.

The present investigation of the South China Sea soft coral Sarcophyton trocheliophorum resulted in the discovery of six new polyoxygenated diterpenes, namely sartrocheliols A-E (1, 3, 5-8) along with four known ones, 2, 4, 9, and 10. Based on extensive spectroscopic data analysis, sartrocheliol A (1) was identified as an uncommon capnosane diterpene, while sartrocheliols B-E (3, 5-8) were established as cembrane diterpenes. They displayed diverse structural features not only at the distinctly different carbon frameworks but also at the various types of heterocycles, including the epoxide, γ-lactone, furan, and pyran rings. Moreover, their absolute configurations were determined by a combination of quantum mechanical-nuclear magnetic resonance (QM-NMR) approach, modified Mosher's method, and X-ray diffraction analysis. In the anti-tumor bioassay, compound 4 exhibited moderate cytotoxic activities against A549, H1975, MDA-MB-231, and H1299 cells with the IC50 values ranging from 26.3 to 47.9 µM.

Guided Isolation of An Uncommon Cembranoid Orthoester, Sarcotortin A, and Three Skeletal Diverse Terpenoids from the Hainan Soft Coral Sarcophyton tortuosum Based on Molecular Networking Strategy.

Applying the emerging molecular networking strategy, an uncommon cembranoid orthoester, sarcotortin A (1), featuring a 3/14/8/5-fused scaffold, an unusual eunicellane-type diterpenoid, sarcotorolide A (2), and two new biscembranoids, ximaolides M and N (7 and 8), along with nine known terpenoids 3-6 and 9-13 were isolated from the Hainan soft coral Sarcophyton tortuosum. The structure and absolute configuration of all new compounds were established by a combination of spectroscopic data, X-ray diffraction analysis, and/or quantum chemical computational approaches. The plausible biogenetic relationship among these skeletally different terpenoids was proposed and discussed. In in vitro bioassay, new compound 7 exhibited a remarkable inhibitory activity against protein tyrosine phosphatases 1B (PTP1B) with the IC50 value of 8.06 µM. In addition, compounds 4 and 10 displayed significant inhibitory effects on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophages cells with the IC50 values of 19.13 and 16.45 µM, respectively. Compound 9 showed interesting cytotoxicity against H1975, MDA-MB231, A549, and H1299 cancer cell lines with IC50 values of 31.59, 34.96, 43.87, and 27.93 µM, respectively.

Neuroprotective effects of a lead compound from coral via modulation of the orphan nuclear receptor Nurr1.

AIMS: To screen coral-derived compounds with neuroprotective activity and clarify the potential mechanism of lead compounds. METHODS: The lead compounds with neuroprotective effects were screened by H2 O2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP+ )-induced cell damage models in SH-SY5Y cells. CCK8 and LDH assays were used to detect cell viability. The anti-apoptosis of lead compounds was evaluated by flow cytometry. JC-1 and MitoSox assays were performed to examine the changes in mitochondrial membrane potential and mitochondrial ROS level. Survival of primary cortical and dopaminergic midbrain neurons was measured by MAP2 and TH immunoreactivities. The Caenorhabditis elegans (C. elegans) model was established to determine the effect of lead compounds on dopaminergic neurons and behavior changes. RESULTS: Three compounds (No. 63, 68, and 74), derived from marine corals, could markedly alleviate the cell damage and notably reverse the loss of worm dopaminergic neurons. Further investigation indicated that compound 63 could promote the expression of Nurr1 and inhibit neuronal apoptosis signaling pathways. CONCLUSION: Lead compounds from marine corals exerted significant neuroprotective effects， which indicated that coral might be a new and potential resource for screening and isolating novel natural compounds with neuroprotective effects. Furthermore, this study also provided a new strategy for the clinical treatment of neurodegenerative diseases such as Parkinson's disease.

Bioactive Cembranoids from the Coral Sarcophyton trocheliophorum of Ximao Island.

Eight new cembranoids (sarcophytembranoids A-H, 1-8) and 10 known terpenoids (9-18) were obtained from the soft coral Sarcophyton trocheliophorum of Ximao Island. Notably, 11, 15, and 16 were obtained from a natural source for the first time. The structures of the new isolates were elucidated by extensive spectroscopic analysis, optical rotatory dispersion, and X-ray diffraction experiments. Although the isolated compounds did not show significant activity against the tested tumor cell lines, compounds 3, 7, 8, and 10-15 exhibited anti-inflammatory activities at 10 µM, and compounds 17 and 18 showed moderate protein tyrosine phosphatase 1B inhibition activities with the minimum inhibitory concentrations of 22.19 and 11.26 µM, respectively.

Ocellatuperoxides A-F, Uncommon Anti-Tumoral γ-Pyrone Peroxides from a Photosynthetic Mollusk Placobranchus ocellatus.

Six new pairs of γ-pyrone polypropionate enantiomers with an unusual peroxyl bridge at the side chain, namely (±)-ocellatuperoxides A-F (1-6), were isolated and characterized from the South China Sea photosynthetic mollusk Placobranchus ocellatus. Extensive spectroscopic analysis, single crystal X-ray diffraction analysis, ECD- (electronic circular dichroism) comparison, and TDDFT (time-dependent density functional theory) ECD computation were used to determine the structures and absolute configurations of new compounds. In a cell viability assay, several compounds showed considerable anti-tumoral effects on human non-small cell lung cancer cells A549 with Gefitinib (7.4 µM) and Erlotinib (2.1 µM) as positive controls. Further RNA-sequencing analysis and gene expression evaluation indicated that the anti-tumoral activity of the most effective compound 3 was associated with the regulation of several important genes, such as FGFR1 and HDAC5.

New flexible cembrane-type macrocyclic diterpenes as TNF-α inhibitors from the South China Sea soft coral Sarcophyton mililatensis.

A further study on the rarely reported soft coral Sarcophyton mililatensis disclosed five new flexible cembrane-type macrocyclic diterpenes sarcomililatols C-G (1-5) and two known analogues 6 and 7. The structures and absolute configurations of natural macrocyclic compounds 1-6 were established by the extensive spectroscopic analysis, X-ray diffraction analysis, time-dependent density functional theory/electronic circular dichroism (TDDFT ECD) calculations, chemical reaction, and modified Mosher's method. In the bioassays, the macrocyclic diterpene 2 exhibited potent TNF-α inhibition (IC50 = 6.1 µmol/L), which was better than the positive control dexamethasone (IC50 = 8.7 µmol/L), and no obvious cytotoxicity against RAW264.7 cells with CC50 values over 50 µmol/L, indicating natural macrocyclic compound 2 could be served as a model compound to develop a new and prospective chemotype of an anti-inflammatory lead compound or drug candidate.

Mililatensols A-C, New Records of Sarsolenane and Capnosane Diterpenes from Soft Coral Sarcophyton mililatensis.

Three unusual diterpenes with rare sarsolenane and capnosane skeletons, namely mililatensols A-C (1-3), were isolated from the South China Sea soft coral Sarcophyton mililatensis, leading to the first record of sarsolenane and capnosane diterpenes from the title animal. The structures of compounds 1-3 were established by extensive spectroscopic analysis and comparison with the literature data. Moreover, the absolute configuration of 2 was determined by TDDFT ECD calculations. In an in vitro bioassay, none of the isolated compounds showed obvious anti-inflammatory activity on LPS-induced TNF-α release in RAW264.7 macrophages. In the preliminary virtual screening of inhibitory potential against SARS-CoV-2 by molecular docking, the results showed these three diterpenes were potential SARS-CoV-2 Mpro inhibitors.

Design, synthesis and in vitro biological evaluation of marine phidianidine derivatives as potential anti-inflammatory agents.

Phidianidines A and B are novel marine indole alkaloids with various biological activities. Based on their potential anti-inflammatory properties, a series of phidianidine derivatives were designed, synthesized, and tested for their effects on IL-17A production in PMA/ionomycin-stimulated T-cell-lymphoma EL-4 cells. Compounds 9a and 22c exhibited excellent anti-inflammatory activity and low toxicity, with IC50 values of 7.7 µM and 5.3 µM for IL-17A production in PMA/ionomycin-stimulated EL-4 cells, respectively. Further mechanistic study showed that 9a could decrease the STAT3 phosphorylation at Y705 to inhibit IL-17A production in EL-4 cells, indicating its ability of preventing the differentiation of Th17 cells and their possible function. This research may give an insight for the discovery of marine indole alkaloid derived anti-inflammatory drug leads for the treatment of T cell-mediated diseases.