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.

Nine New Antibacterial Diterpenes and Steroids from the South China Sea Soft Coral Lobophytum catalai Tixier-Durivault.

Five new cembrane-type diterpenes, lobocalines A-E (1-5), and four new steroids, lobocaloids A-D (9-12), along with six known related compounds (6-8 and 13-15) were isolated from the Yalong Bay soft coral Lobophytum catalai Tixier-Durivault. The structures of the new compounds were elucidated by extensive spectroscopic analysis, NMR calculation with DP4+ analysis, time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD) calculations, X-ray diffraction analyses and comparison with the reported spectroscopic data of known compounds. Further, with the aid of X-ray diffraction analysis, the structure of lobocrasol B (15) was firmly revised as 15a. In in vitro bioassays, compound 2 showed moderate antibacterial activities against fish pathogenic bacteria Streptococcus parauberis KSP28 and Phoyobacterium damselae FP2244 with minimum inhibitory concentration (MIC) values of 8.7 and 17.3 µg/mL, respectively. All the steroids exhibited antibacterial activities against the S. parauberis KSP28 with MIC values ranging from 12.3 to 53.6 µg/mL. Compounds 2, 7 and 14 have remarkable inhibitory effects on the hemolysin production of Staphylococcus aureus, while compounds 8-12 have medium inhibitory effects on the pyocyanin production in Pseudomonas aeruginosa.

Four uncommon cycloamphilectane-type diterpenoids with antibacterial activity from the South China Sea soft coral Sinularia brassica.

The chemical investigation on the soft coral Sinularia brassica collected off Xuwen Country, Guangdong Province, China, has resulted in the isolation and characterization of three uncommon cycloamphilectane-type diterpenoids, namely sinucycloamtin A-C (1-3), along with two known analogues (5 and 6). In addition, compounds 2 and 3 were hydrolyzed and their hydrolytic derivative sinucycloamtin D (4) was obtained. The structures of these previously undescribed compounds were established on the basis of extensive spectroscopic analysis, X-ray diffraction analysis, chemical conversion, as well as the comparison with the literature reported data. Compounds 1-3 represented the first examples of benzene-containing cycloamphilectane-type diterpenoids isolated from soft coral of genus Sinularia. In the in vitro bioassays, all the isolated and derived diterpenoids exhibited significant antibacterial activities against the fish pathogenic bacteria Phoyobacterium damselae FP2244 and Streptococcus parauberis SPOF3K with MIC90 values ranging from 3.7 to 9.1 µM.

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.

Lobosteroids A-F: Six New Highly Oxidized Steroids from the Chinese Soft Coral Lobophytum sp.

To explore the steroidal constituents of the soft coral Lobophytum sp. at the coast of Xuwen County, Guangdong Province, China, a chemical investigation of the above-mentioned soft coral was carried out. After repeated column chromatography over silica gel, Sephadex LH-20, and reversed-phase HPLC, six new steroids, namely lobosteroids A-F (1-6), along with four known compounds 7-10, were obtained. Their structures were determined by extensive spectroscopic analysis and comparison with the spectral data reported in the literature. Among them, the absolute configuration of 1 was determined by X-ray diffraction analysis using Cu Kα radiation. These steroids were characterized by either the presence of an α,ß-α',ß'-unsaturated carbonyl, or an α,ß-unsaturated carbonyl moiety in ring A, or the existence of a 5α,8α-epidioxy system in ring B, as well as diverse oxidation of side chains. The antibacterial bioassays showed that all isolated steroids exhibited significant inhibitory activities against the fish pathogenic bacteria Streptococcus parauberis FP KSP28, Phoyobacterium damselae FP2244, and Streptococcus parauberis SPOF3K, with IC90 values ranging from 0.1 to 11.0 µM. Meanwhile, compounds 2 and 6-10 displayed potent inhibitory effects against the vancomycin-resistant Enterococcus faecium bacterium G7 with IC90 values ranging from 4.4 to 18.3 µM. Therefore, ten highly oxidized steroids with strong antibacterial activities were isolated from the Chinese soft coral Lobophytum sp., which could be developed as new chemotypes of antibacterial drug leads.

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 Protolimonoids from the Chinese Mangrove Xylocarpus granatum Koenig.

Two new compounds including one apotirucallane protolimonoid, xylogranatriterpin A (1), and one glabretal protolimonoid, xylocarpusin A (2), along with three known related compounds were isolated from the twigs and leaves of the Chinese mangrove Xylocarpus granatum. The apotirucallane xylogranatriterpin A (1) bears an unprecedented 24-ketal carbon connecting ring E with an epoxide ring. The structures of new compounds were elucidated by extensive spectroscopic analysis and by comparison of the spectroscopic data with those reported in the literatures. Plausible biosynthetic pathway to xylogranatriterpin A (1) was also proposed. None of them showed cytotoxic, neuroprotective, or protein tyrosine phosphatase 1B (PTP1B) inhibitory activity.

New Antibacterial Diterpenoids from the South China Sea Soft Coral Klyxum molle.

Fifteen new diterpenoids, namely xishaklyanes A-O (1-15), along with three known related ones (16-18), were isolated from the soft coral Klyxum molle collected from Xisha Islands, South China Sea. The stereochemistry of the new compounds was elucidated by a combination of detailed spectroscopic analyses, chemical derivatization, quantum chemical calculations, and comparison with the reported data. The absolute configuration of compound 18 was established by the modified Mosher's method for the first time. In bioassay, some of these compounds exhibited considerable antibacterial activities on fish pathogenic bacteria, and compound 4 showed the most effective activity with MIC of 0.225 µg/mL against Lactococcus garvieae.

Oxygenated Cembrane Diterpenes from the South China Sea Soft Coral Sinularia tumulosa.

The chemical investigation of the rarely studied soft coral Sinularia tumulosa resulted in the discovery of five oxygenated cembrane diterpenes 1-5, including two new compounds situmulins A (1) and B (2). The structures of 1 and 2 were established through the extensive analyses of 1D and 2D NMR spectral data together with the comparisons with the known compounds. Furthermore, the absolute configuration of 1 was determined by the time-dependent density functional theory (TDDFT) ECD approach, while the relative configuration of 2 was assigned via the quantum mechanical-NMR (QM-NMR) calculations. It might be worth to point out it is the first time to disclose the presence of cembrane diterpenes in the title species. In the bioassays, compound 2 not only showed strong antibacterial activities against fish pathogenic bacteria Streptococcus parauberis FP KSP28 and Phoyobacterium damselae FP2244 with both minimum inhibitory concentration for 90 % (MIC90 ) values of 25 µM, but also demonstrated substantial inhibitory efficacy against vancomycin-resistant Enterococcus faecium bacteria G1, G4, G7, G8 and G13 from several individuals, with MIC90 values of 25, 50, 100, 50 and 25 µM, respectively.

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).

Design, Synthesis and Biological Evaluation of 6-(Imidazo[1,2-a]pyridin-6-yl)quinazoline Derivatives as Anticancer Agents via PI3Kα Inhibition.

Aberrant expression of the phosphatidylinositol 3-kinase (PI3K) signalling pathway is often associated with tumourigenesis, progression and poor prognosis. Hence, PI3K inhibitors have attracted significant interest for the treatment of cancer. In this study, a series of new 6-(imidazo[1,2-a]pyridin-6-yl)quinazoline derivatives were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS spectra analyses. In the in vitro anticancer assay, most of the synthetic compounds showed submicromolar inhibitory activity against various tumour cell lines, among which 13k is the most potent compound with IC50 values ranging from 0.09 µΜ to 0.43 µΜ against all the tested cell lines. Moreover, 13k induced cell cycle arrest at G2/M phase and cell apoptosis of HCC827 cells by inhibition of PI3Kα with an IC50 value of 1.94 nM. These results suggested that compound 13k might serve as a lead compound for the development of PI3Kα inhibitor.

Chemistry, Chemo-Ecology, and Biological Activities of Uncommon and Structurally Diverse Sesquiterpenoids from the Sanya Bay Nudibranch Hexabranchus sanguineus.

A detailed chemical investigation of the Sanya Bay nudibranch Hexabranchus sanguineus yielded thirteen new sesquiterpenoids, namely sanyagunins A-H, sanyalides A-C, and sanyalactams A and B, along with eleven known related ones. Sanyalactams A and B feature an unprecedented hexahydrospiro[indene-2,3'-pyrrolidine] core. The structures of new compounds were established by a combination of extensive spectroscopic data analysis, quantum mechanical-nuclear magnetic resonance methods, the modified Mosher's method, and X-ray diffraction analysis. Based on analysis of NOESY correlations and the modified Mosher's method, the stereochemistry of two known furodysinane-type sesquiterpenoids were revised. A plausible biogenetic relationship between these sesquiterpenoids wasproposed and discussed, and a chemo-ecological relationship of the title animal and its possible sponge preys has been analyzed. In bioassays, sanyagunin B showed moderate antibacterial activity, whereas 4α-formamidogorgon-11-ene exhibited potent cytotoxicity with IC50 values ranging from 0.87 to 1.95 µM.

Design, synthesis, and biological evaluation of 6-(imidazo[1,2-a] pyridin-6-yl) quinazolin-4(3H)-one derivatives as potent anticancer agents by dual targeting Aurora kinase and ROR1.

ROR1 and Aurora kinase were overexpressed in various cancers and essential for cell proliferation, survive and metastasis. Pharmaceutical inhibition of ROR1 and Aurora kinase abrogated the activation of downstream signaling and induced cancer cell apoptosis. Hence, ROR1 and Aurora kinase considered as attractive therapeutic targets for the development of anticancer drugs. In the present work, three series of novel 6-(imidazo[1,2-a] pyridin-6-yl)-quinazolin-4(3H)-one derivatives were designed and synthesized via bioisosterism and scaffold-hopping strategies guided by FLF-13, an Aurora kinase inhibitor we discovered earlier. Most of compounds in series 2 and series 3 showed submicromolar to nanomolar inhibitory activity against multiple cancer cell lines. More importantly, compounds 12d and 12f in series 3 showed nanomolar inhibitory activity against all test cancer cells. The most promising compound 12d exhibited potent inhibitory activity against Aurora A and Aurora B with IC50 values of 84.41 nM and 14.09 nM, respectively. Accordingly, compounds 12d induced G2/M phase cell cycle arrest at 24 h and polyploidy at 48 h. It's worth noting that 12d also displayed inhibitory activity against ROR1 and induce cell apoptosis. Furthermore, 12d could significantly inhibit the tumor growth in SH-SY5Y xenograft model with tumor growth inhibitory rate (IR) up to 46.31 % at 10 mg/kg and 52.66 % at 20 mg/kg. Overall, our data suggested that 12d might serve as a promising candidate for the development of therapeutic agents for cancers with aberrant expression of ROR1 and Aurora kinases by simultaneously targeting ROR1 and Aurora kinase.

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.

Structure optimization, synthesis, and biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H)-one derivatives as potential multi-targeted anticancer agents via Aurora A/ PI3K/BRD4 inhibition.

Aurora A (Aurora kinase A), a critical regulator of cell mitosis, is frequently overexpressed in many malignant cancers, and has been considered as a promising drug target for cancer therapy. Likewise, Phosphatidylinositol 3-kinase alpha (PI3Kα) is also regarded as one of the most important targets in cancer therapy by mediating the cell growth and angiogenesis of various human cancers. In addition, Bromodomain-containing protein 4 (BRD4) modulates oncogene expressions of Myc, Aurora kinase and various RTKs. Recently, accumulating evidences indicated that hyperactivated or abnormally expressed Aurora A, PI3Kα or BRD4 are closely associated with drug resistance and poor prognosis of non-small cell lung cancer (NSCLC). Hence, simultaneous inhibition of Aurora A, PI3Kα, and BRD4 is expected to be a new strategy for NSCLC therapy. In this study, we performed further structure optimization of 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H) -one based on previous study to obtain a series of derivatives for discovering potential Aurora A, PI3Kα and BRD4 multi-targeted inhibitors. MTT assay showed that most of the newly synthesized compounds exhibited an evident anticancer activity against the NSCLC cells. Among them, the IC50 values of the most potent compound 9a were 0.83, 0.26 and 1.02 µM against A549, HCC827 and H1975 cells, respectively. In addition, 9a markedly inhibited the Aurora A and PI3Kα kinase activities with IC50 values of 10.19 nM and 13.12 nM. Compound 9a induced G2/M phase arrests and apoptosis of HCC827 cells by simultaneous inhibition of Aurora A/PI3K/ BRD4 signaling pathways. Collectively, our studies suggested that 9a might be a potential multi-targeted inhibitor for NSCLC therapy.

Structurally Diverse Diterpenoids from the Sanya Bay Nudibranch Hexabranchus sanguineus and Its Sponge-Prey Chelonaplysilla sp.

Investigation of the South China Sea nudibranch Hexabranchus sanguineus from Sanya Bay afforded, in addition to three known compounds, nine new diterpenoids of the 5,19-cycloclerodane- (sanyanolides A-D), clerodane- (sanyanolide E) and subersin- (sanyanolides F-I) type. Remarkably, six diterpenoids aforementioned from H. sanguineus were also isolated from the sponge Chelonaplysilla sp. from the same water region, suggesting a trophic relationship between H. sanguineus and Chelonaplysilla sp. The structure and absolute configuration of new compounds were established by a combination of spectroscopic data, X-ray diffraction analysis and/or time-dependent density functional theory/electronic circular dichroism calculations. A plausible biogenetic relationship between these diterpenoids, along with the chemo-ecological implications of their co-occurrence in the two organisms investigated, was proposed and discussed. In in vitro bioassays, echinoclerodane A exhibited a potent inhibitory effect (IC50 =2.81 µM) on LPS-induced inflammatory response in RAW 264.7 macrophage cells. In addition, echinoclerodane A and oculatolide showed considerable antibacterial activities with MIC values ranging from 1.0 to 8.0 µg/mL.

Hyrtiosins F and G, two new scalarane sesterterpenes from the South China sea sponge Hyrtios erecta.

Two new scalarane sesterterpenes, hyrtiosins F and G (1 and 2), along with two known related compounds, hyrtiosin D and sesterstatin 6 (3 and 4), were isolated from the Hainan marine sponge Hyrtios erecta. The structures of new compounds 1 and 2 were determined by detailed analysis of 1D and 2D NMR spectra and by comparison of the spectroscopic data with those reported in the literatures.