RESUMO
Cembranolides are characteristic metabolites in marine soft corals, with complex structures and widespread biological activities. However, seldom has an intensive pharmacological study been done for these intriguing marine natural products. In this work, systematic chemical investigation was performed on Sinularia pedunculata by HSQC-based small molecule accurate recognition technology (SMART), resulting in the isolation and identification of 31 cembrane-type diterpenoids, including six new ones. In the bioassay, several compounds showed significant anti-inflammatory activities on the inhibition of NO production. The structure-activity relationship (SAR) was comprehensively analyzed, and two most bioactive and less toxic compounds 8 and 9 could inhibit inflammation through suppressing NF-κB and MAPK signaling pathways, and reduce the secretion of inflammatory cytokines. In a mouse model of dextran sodium sulfate (DSS)-induced acute colitis, 8 and 9 exhibited good anti-inflammatory effects and the ability to repair the colon epithelium, giving insight into the application of cembranolides as potential ulcerative colitis (UC) agents.
Assuntos
Antozoários , Colite Ulcerativa , Sulfato de Dextrana , Diterpenos , Animais , Colite Ulcerativa/tratamento farmacológico , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/uso terapêutico , Diterpenos/isolamento & purificação , Camundongos , Relação Estrutura-Atividade , Antozoários/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/isolamento & purificação , Células RAW 264.7 , NF-kappa B/metabolismo , NF-kappa B/antagonistas & inibidores , Descoberta de Drogas , Camundongos Endogâmicos C57BL , Humanos , Masculino , Óxido Nítrico/metabolismoRESUMO
A detailed chemical investigation of the Hainan soft coral Lobophytum crassum led to the identification of a class of polyoxygenated cembrane-type macrocyclic diterpenes (1-28), including three new flexible cembranoids, lobophycrasins E-G (2-4), and twenty-five known analogues. Their structures were elucidated by combining extensive spectroscopic data analysis, quantum mechanical-nuclear magnetic resonance (QM-NMR) methods, the modified Mosher's method, X-ray diffraction analysis, and comparison with data reported in the literature. Bioassays revealed that sixteen cembranoids inhibited the proliferation of H1975, MDA-MB231, A549, and H1299 cells. Among them, Compounds 10, 17, and 20 exhibited significant antiproliferative activities with IC50 values of 1.92-8.82 µM, which are very similar to that of the positive control doxorubicin. Molecular mechanistic studies showed that the antitumour activity of Compound 10 was closely related to regulation of the ROR1 and ErbB3 signalling pathways. This study may provide insight into the discovery and utilization of marine macrocyclic cembranoids as lead compounds for anticancer drugs.
RESUMO
Eunicellane diterpenoids, containing a typical 6,10-bicycle, are bioactive compounds widely present in marine corals, but rarely found in bacteria and plants. The intrinsic macrocycle exhibits innate structural flexibility resulting in dynamic conformational changes. However, the mechanisms controlling flexibility remain unknown. The discovery of a terpene synthase, MicA, that is responsible for the biosynthesis of a nearly non-flexible eunicellane skeleton, enable us to propose a feasible theory about the flexibility in eunicellane structures. Parallel studies of all eunicellane synthases in nature discovered to date, including 2Z-geranylgeranyl diphosphate incubations and density functional theory-based Boltzmann population computations, reveale that a trans-fused bicycle with a 2Z-configuration alkene restricts conformational flexibility resulting in a nearly non-flexible eunicellane skeleton. The catalytic route and the enzymatic mechanism of MicA are also elucidated by labeling experiments, density functional theory calculations, structural analysis of the artificial intelligence-based MicA model, and mutational studies.
Assuntos
Alquil e Aril Transferases , Diterpenos , Alquil e Aril Transferases/metabolismo , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/química , Diterpenos/metabolismo , Diterpenos/química , Fosfatos de Poli-Isoprenil/metabolismo , Fosfatos de Poli-Isoprenil/química , Modelos MolecularesRESUMO
Hepatitis B Virus (HBV) infection is a global public health challenge that seriously endangers human health. Soft coral, as a major source of terpenoids, contains many structurally novel and highly bioactive compounds. Sixteen cembranoids (1-16), including a new one named sinupedunol B (16), were isolated from the South China Sea Soft coral Sinularia pedunculata. The structure of the sinupedunol B (16) was determined through a combination of spectroscopic analysis and X-ray single-crystal diffraction. In this study, cembranoids isolated from Sinularia pedunculata were found of anti-HBV activity for the first time. Among them, flexilarin D (6) showed significant anti-HBV activity with an IC50 value of 5.57â µM without cytotoxicity. We then analyzed the structure-activity relationship (SAR). Furthermore, it is demonstrated that flexilarin D (6) can accelerate the formation of capsid, inhibit HBeAg, HBV core particle DNA, HBV total RNA and pregenomic RNA in a dose dependent manner. We also confirmed the anti-HBV activity of 6 in HepG2-NTCP infection system. Finally, we demonstrated the anti-HBV mechanism of these compounds by inhibiting the ENI/Xp enhancer/promoter.
RESUMO
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.
Assuntos
Antozoários , Sesquiterpenos , Antozoários/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Animais , Camundongos , Estrutura Molecular , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , China , Células RAW 264.7 , Testes de Sensibilidade Microbiana , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Relação Estrutura-Atividade , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Teoria da Densidade Funcional , Relação Dose-Resposta a DrogaRESUMO
One new highly degraded steroid, namely 21-nor-4-ene-chaxine A (1) furnishing a 5/6/5-tricyclic, along with one known related analogue (2), were isolated from the South China Sea sponge Spongia officinalis. Their structures including absolute configurations were established by extensive spectroscopic data analysis, TDDFT-ECD calculation, and comparison with the spectral data previously reported in the literature. Compound 1 represent the new member of incisterols family with a highly degradation in ring B. In vitro bioassays revealed compound 2 exhibited significant anti-microglial inflammatory effect on lipopolysaccharide (LPS)-induced inflammation in BV-2 microglial cells.
Assuntos
Anti-Inflamatórios , Lipopolissacarídeos , Poríferos , Esteroides , Animais , Poríferos/química , Esteroides/química , Esteroides/isolamento & purificação , Esteroides/farmacologia , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , China , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/citologia , Linhagem Celular , Conformação Molecular , Estrutura MolecularRESUMO
Penicillium strains are renowned for producing diverse secondary metabolites with unique structures and promising bioactivities. Our chemical investigations, accompanied by fermentation media optimization, of a newly isolated fungus, Penicillium shentong XL-F41, led to the isolation of twelve compounds. Among these are two novel indole terpene alkaloids, shentonins A and B (1 and 2), and a new fatty acid 3. Shentonin A (1) is distinguished by an unusual methyl modification at the oxygen atom of the typical succinimide ring, a feature not seen in the structurally similar brocaeloid D. Additionally, shentonin A (1) exhibits a cis relationship between H-3 and H-4, as opposed to the trans configuration in brocaeloid D, suggesting a divergent enzymatic ring-expansion process in their respective fungi. Both shentonins A (1) and B (2) also feature a reduction of a carbonyl to a hydroxy group within the succinimide ring. All isolated compounds were subjected to antimicrobial evaluations, and compound 12 was found to have moderate inhibitory activity against Candia albicans. Moreover, genome sequencing of Penicillium shentong XL-F41 uncovered abundant silent biosynthetic gene clusters, indicating the need for future efforts to activate these clusters and unlock the full chemical potential of the fungus.
RESUMO
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.
Assuntos
Proteínas Serina-Treonina Quinases , Sepse , Animais , Camundongos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fator de Iniciação 4E em Eucariotos/química , Baço , Interleucina-6/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Sepse/tratamento farmacológico , Piridinas/metabolismo , FosforilaçãoRESUMO
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.
Assuntos
Antozoários , Reabsorção Óssea , Diterpenos , Animais , Osteogênese , Fosfatidilinositol 3-Quinases/metabolismo , Diferenciação Celular , Osteoclastos , NF-kappa B/metabolismo , Inflamação/metabolismo , Antozoários/metabolismo , Ligante RANK/metabolismo , Fatores de Transcrição NFATC/metabolismoRESUMO
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.
Assuntos
Antozoários , Diterpenos , Animais , Esteroides/farmacologia , Antibacterianos/farmacologia , Espectroscopia de Ressonância Magnética , Antozoários/química , Diterpenos/química , China , Estrutura MolecularRESUMO
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.
Assuntos
Antozoários , Brassica , Diterpenos , Animais , Estrutura Molecular , Antozoários/química , Diterpenos/química , ChinaRESUMO
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.
Assuntos
Antozoários , Antineoplásicos , Produtos Biológicos , Animais , Terpenos/química , Antibacterianos/farmacologia , Antineoplásicos/metabolismo , Antozoários/química , Produtos Biológicos/químicaRESUMO
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.
Assuntos
Antozoários , Diterpenos , Animais , Humanos , Estrutura Molecular , Antozoários/química , Linhagem Celular Tumoral , Diterpenos/farmacologia , Diterpenos/química , ChinaRESUMO
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.
Assuntos
Antozoários , Animais , Humanos , População do Leste Asiático , Antibacterianos/farmacologia , Esteroides/farmacologiaRESUMO
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.
RESUMO
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.
Assuntos
Antozoários , Antineoplásicos , Animais , Anti-Inflamatórios/farmacologia , Bioensaio , ChinaRESUMO
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.
Assuntos
Limoninas , Meliaceae , Triterpenos , Limoninas/química , Meliaceae/química , Estrutura Molecular , Triterpenos/químicaRESUMO
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.
Assuntos
Antozoários , Diterpenos , Animais , Antozoários/química , Diterpenos/química , China , Antibacterianos/farmacologia , Estrutura MolecularRESUMO
Three new steroids, along with two known related analogs, were isolated from the Xisha Island soft coral Lobophytum sarcophytoides. The structures and absolute configurations of the new compounds were elucidated by extensive spectroscopic data analyses, time dependent density functional theory electronic circular dichroism calculation, and comparison with the spectral data previously reported in the literature. In inâ vitro bioassay, four compounds showed interesting suppressive effects on lipopolysaccharide (LPS) induced inflammation in BV-2 microglial cells at 10â µM level.
Assuntos
Antozoários , Diterpenos , Animais , Antozoários/química , Esteroides/farmacologia , Esteroides/química , Anti-Inflamatórios/farmacologia , China , Lipopolissacarídeos/farmacologia , Diterpenos/química , Estrutura MolecularRESUMO
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 H1299â cell (IC50 =35.0â µM), whereas sarcomililatin B and sarcomililatin A displayed moderate antibacterial activities (MIC 17.4-34.8â µg/mL).