ABSTRACT
A formerly unpublicized briarane diterpenoid, briastecholide M (1), and its established analogue, brianodin B (2), were purified from Briareum stechei, an octocoral collected from Okinawan waters. Using spectroscopic methods, the structure of 1 was established. Functional study showed that 1 can reducing the release of inducible nitric oxide synthase (iNOS) but enhancing cyclooxygenase-2 (COX-2) protein expression.
Subject(s)
Anthozoa , Diterpenes , Animals , Anthozoa/chemistry , Anthozoa/metabolism , Diterpenes/pharmacology , Diterpenes/chemistry , Nitric Oxide Synthase Type II/metabolism , Cyclooxygenase 2/metabolismABSTRACT
The chemical screening of a cultured soft coral, Briareum violaceum, led to the isolation of eight natural, briarane-related diterpenoids, including three unreported metabolites, briavioids E-G (1-3), and five known briaranes, briacavatolides B (4) and C (5), briaexcavatin L (6), briaexcavatolide U (7) and briarenol K (8). The structures of briaranes 1-8 were established using spectroscopic methods. The absolute configuration of briavioid A (9), obtained in a previous study, was reported for the first time in this study by a single-crystal X-ray diffraction analysis using a copper radiation source. The anti-inflammatory activity of briaranes 1 and 2 and briaranes 4-8 was evaluated by screening their inhibitory ability against the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells.
Subject(s)
Anthozoa , Diterpenes , Animals , Mice , Anti-Inflammatory Agents/pharmacology , RAW 264.7 Cells , Macrophages/metabolism , Diterpenes/pharmacology , Anthozoa/chemistry , Nitric Oxide Synthase Type II/metabolism , Cyclooxygenase 2/metabolismABSTRACT
Chemoinformatic and bioassay-guided fractionation of a gorgonian coral Junceella juncea resulted in the isolation of 45 briarane-type diterpenoids, of which 16 new analogues were characterized. Their structures were identified by extensive analyses of the spectroscopic data. Most isolated briaranes showed significant inhibition against the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow-derived macrophages cells (BMMs). Praelolide, one of the active analogues, significantly activates nuclear factor erythroid-2-related factor 2 (Nrf2) nucleus translocation, induces the expression of Nrf2-targeted genes, suppresses reactive oxygen species (ROS) production, abrogates the activation of downstream mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NFκB) signaling, and subsequently attenuates osteoclast differentiation. Mechanically, praelolide interacts with Kelch-like ECH-associated protein 1 (Keap1) protein by non-covalent interaction to interrupt the interaction between Keap1 and Nrf2 and thereby to activate the Nrf2 signaling pathway. In addition, praelolide rescues the bone loss in prednisone-induced zebrafish. The present study provided praelolide as a new natural scaffold to remedy osteoclastogenic bone disease.
Subject(s)
Diterpenes , Osteoclasts , Animals , Diterpenes/pharmacology , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Osteoclasts/metabolism , Reactive Oxygen Species/metabolism , Zebrafish/metabolism , MacrophagesABSTRACT
A known polyoxygenated briarane, briaexcavatolide P (1), was isolated from a Formosan octocoral Briareum stechei. Moreover, the same species B. stechei, collected from Okinawan waters, yielded three chlorine-containing briaranes, including two new compounds, briastecholides B (2) and C (3) as well as a known analogue, briarenol R (4). The structures of 1-4 were established using spectroscopic methods. In addition, briarane 1 demonstrated anti-inflammatory activity in lipo-polysaccharide-induced RAW 264.7 mouse macrophage cells by suppressing the expression of inducible nitric oxide synthase (iNOS) protein.
Subject(s)
Anthozoa/chemistry , Diterpenes/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Diterpenes/pharmacology , Mice , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/metabolism , RAW 264.7 CellsABSTRACT
Excess osteoclastic activity leads to an imbalance in bone remodeling and causes most adult skeletal diseases. Natural products are a promising source to attenuate the osteoporosis and relevant diseases of bone loss. Herein, a bioassay-guided detection of gorgonian corals resulted in junceellolide D (JD), a briarane-type diterpenoid from gorgonian Dichotella gemmacea, showing significant inhibition against the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs) in vitro. To extend the investigation for structure-activity relationship (SAR), a total of 39 briarane-type analogues were isolated including 28 new compounds, and their structures were determined by extensive analyses of spectroscopic data. The SAR data indicated that JD is the most active to inhibit osteoclast development due to the decreased number of multinucleated tartrate-resistance acid phosphatase positive cells, suppression of the actin ring formation, blockage of bone resorption, and downregulation of osteoclast-specific marker genes. Mechanistically, JD increased the protein stability of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2) and promoted Nrf2 nuclear translocation followed by activation its downstream antioxidant enzymes, which strongly abolished RANKL-induced generation of reactive oxygen species (ROS). Furthermore, JD inhibits the RANKL-stimulated activation of NF-κB and MAPK signaling pathways. Hence, JD is considered as a promising lead compound for anti-osteoclastogenesis via activating Nrf2 and suppressing NF-κB and MAPK signaling pathways to prevent osteoclast-mediated bone destructive diseases.
Subject(s)
Anthozoa/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , NF-E2-Related Factor 2/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Osteogenesis/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Dose-Response Relationship, Drug , Humans , MAP Kinase Signaling System/drug effects , Molecular Structure , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
Chemical investigation of the octocoral Briareum stechei, collected in the Ie Island, Okinawa, Japan, resulted in the isolation of a new briarane-type diterpenoid, briastecholide A (1), as well as the previously reported metabolites, solenolide C (2) and briarenolide S (3). The structures of briaranes 1-3 were characterized through spectroscopic analysis, and the absolute configuration of 2 was corroborated by a single-crystal X-ray diffraction analysis. Briarane 3 exhibited bioactivity against the protein expression of inducible nitric oxide synthase (iNOS).
Subject(s)
Anthozoa/chemistry , Anti-Inflammatory Agents/isolation & purification , Diterpenes/isolation & purification , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Diterpenes/chemistry , Diterpenes/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Japan , Mice , Nitric Oxide Synthase Type II/genetics , RAW 264.7 Cells , X-Ray DiffractionABSTRACT
Briareum stechei is proven to be a rich source of 3,8-cyclized cembranoids (briarane) with a bicyclo[8.4.0] carbon core. In the present study, four previously unreported briaranes, briarenols W-Z (1-4), along with solenolide A (5), briarenolide M (6), briaexcavatolide F (7), and brianolide (8), were isolated and characterized through spectroscopic analysis, and the absolute configuration of 8 was corroborated by a single-crystal x-ray diffraction analysis. Briaranes 2 and 5 were found to induce significant inflammatory activity in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophage cells by enhancing the expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins.
Subject(s)
Anthozoa/chemistry , Diterpenes/isolation & purification , Animals , Chlorine , Diterpenes/chemistry , Diterpenes/pharmacology , Magnetic Resonance Spectroscopy , Mice , RAW 264.7 CellsABSTRACT
Chemical investigation of a gorgonian coral Ellisella sp. resulted in the isolation of 12 briarane-type diterpenoids, including eight new congeners namely ellisellolides A-H (1-8). Their structures were determined by extensive spectroscopic analysis, aided the calculated ECD data to support the configurational assignment. All compounds were evaluated for the in vitro anti-HBV activities in HepAD38 cell line, while preliminary analyses of the structure-activity relationship demonstrated that junceellolide C featured an 3E,5(16)-diene and a chlorine-substitution at C-6 is the most active congener. Junceellolide C exhibited efficient reduction against the HBV DNA, HBV RNA and HBeAg production with a dose-dependent manner. It also significantly reduced the HBV cccDNA replenishment and promoted the existed HBV cccDNA degradation. These findings suggest junceellolide C to be a transcription inhibitor of cccDNA and a promising lead for the development of new anti-HBV agent.
Subject(s)
Antiviral Agents/pharmacology , Diterpenes/pharmacology , Hepatitis B virus/drug effects , Animals , Anthozoa , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Cell Line, Tumor , Diterpenes/chemistry , Diterpenes/isolation & purification , Dose-Response Relationship, Drug , Hepatitis B virus/genetics , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
HBV infection is a common cause of liver disease with a high burden worldwide. Current therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure. In this study, a structure-based screening of marine natural products from an in-house library was performed to hit HBV inhibitors, and the gorgonian-derived briarane-type diterpenoids showed inhibitory effects against HBV DNA replication in HepAD38 cells. Preliminary analyses of structure-activity relationship demonstrated that a briarane-based scaffold with an 3E,5(16)-diene and a chlorine-substitution at C-6 is required for the anti-HBV activity. Junceellolide B is one of the potent HBV inhibitors exhibiting efficient reduction of HBsAg and HBeAg production in HBV infected HepG2-NTCP cells with a dose-dependent manner (p < 0.001). It also significantly reduced the secreted HBV DNA, HBV RNA, and HBeAg in HepAD38 cells with the EC50 values of 0.83, 2.87 and 7.75 µM, respectively. Mechanistically, junceellolide B potently inhibited HBV RNA transcription without promoting HBV RNA degradation. RNA-seq analysis indicated that junceellolide B significantly decreased HBV cccDNA-transcripted products accompanying stable down-regulation of the expression of RNA polymerase II related host transcription factors (ZBED6 and ZBTB7B). These findings suggest junceellolide B to be a transcription inhibitor of cccDNA and a promising lead for the development of new anti-HBV agent.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Diterpenes/chemistry , Diterpenes/pharmacology , Hepatitis B virus/drug effects , Cell Line , DNA Replication/drug effects , DNA, Viral/genetics , Hepatitis B/drug therapy , Hepatitis B Surface Antigens/metabolism , Hepatitis B e Antigens/metabolism , Hepatitis B virus/genetics , Hepatitis B virus/physiology , HumansABSTRACT
Our continuous chemical study of a cultured octocoral Briareum stechei led to the isolation of four new briarane diterpenoids, briarenols Q-T (1-4). The structures of new metabolites 1-4 were established by spectroscopic methods, and compounds 3 and 4 were found to inhibit the generation of inducible nitric oxide synthase (iNOS) from RAW 264.7 stimulated by lipopolysaccharides (LPS).
Subject(s)
Anthozoa/metabolism , Anti-Inflammatory Agents/pharmacology , Diterpenes/pharmacology , Macrophages/drug effects , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Cyclooxygenase 2/metabolism , Diterpenes/chemistry , Diterpenes/isolation & purification , Lipopolysaccharides/pharmacology , Macrophages/enzymology , Mice , Molecular Structure , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , RAW 264.7 Cells , Structure-Activity RelationshipABSTRACT
Two 11,20-epoxybriaranes, including a known compound, juncenolide K (1), as well as a new metabolite, fragilide X (2), have been isolated from gorgonian Junceella fragilis collected off the waters of Taiwan. The absolute configuration of juncenolide K (1) was determined by single-crystal X-ray diffraction analysis for the first time in this study and the structure, including the absolute configuration of briarane 2 was established on the basis of spectroscopic analysis and compared with that of model compound 1. One aspect of the stereochemistry of the known compound 1 was revised. Briarane 2 was found to enhance the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) release from RAW 264.7 cells.
Subject(s)
Anthozoa/chemistry , Diterpenes/pharmacology , Inflammation Mediators/pharmacology , Animals , Cyclooxygenase 2/metabolism , Diterpenes/chemistry , Diterpenes/isolation & purification , Inflammation Mediators/chemistry , Inflammation Mediators/isolation & purification , Mice , Nitric Oxide Synthase Type II/metabolism , RAW 264.7 Cells , Taiwan , X-Ray DiffractionABSTRACT
Five 8,17-epoxybriaranes, including three new compounds-briarenols I-K (1-3), along with two known analogues, briaexcavatolide P (4) and briaexcavatin P (5), were isolated from the octocoral Briareum excavatum. The structures of briaranes 1-3 were elucidated by spectroscopic methods, including 1D and 2D NMR studies and (+)-HRESIMS. Briarane 4 exerted inhibition effects on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) release from RAW 264.7.
Subject(s)
Anthozoa/chemistry , Anti-Inflammatory Agents/pharmacology , Cyclooxygenase 2/metabolism , Diterpenes/pharmacology , Nitric Oxide Synthase Type II/metabolism , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Diterpenes/chemistry , Diterpenes/isolation & purification , Down-Regulation , Gene Expression Regulation, Enzymologic/drug effects , Mice , Molecular Structure , RAW 264.7 CellsABSTRACT
Ten briarane-type diterpenoids (1-10), including one new stereoisomer 17-epi-junceellolide B (1), were isolated from the MeOH extract of the Vietnamese gorgonian Junceella fragilis. Their structures were elucidated by spectroscopic experiments including 1D and 2D NMR, and HR-QTOF-MS. In addition, the in vitro cytotoxic activity against eight human cancer cell lines (LNCaP, HepG2, KB, MCF-7, SK-Mel2, HL-60, LU-1 and SW480) of all isolated compounds was evaluated by SRB assays.
Subject(s)
Anthozoa/chemistry , Antineoplastic Agents/isolation & purification , Diterpenes/isolation & purification , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cytotoxins/chemistry , Cytotoxins/isolation & purification , Cytotoxins/pharmacology , Diterpenes/chemistry , Humans , Molecular Structure , Spectrum Analysis/methods , VietnamABSTRACT
The chemical constituents of gorgonian Junceella fragilis Ridley, collected from Ximao Island, the South China Sea, were investigated. A new briarane-type diterpenoid, named fragilide Y (1), together with five known compounds (2–6), namely fragilide D (2), cholesterol (3), ergosterol peroxide (4), 2'-deoxythymidine (5) and cis-thyminenol (6), were isolated from the acetone extract of J. fragilis. The structure of the new compound 1 was elucidated by extensive spectroscopic analysis, while the known compounds were identified by comparison with the reported data. In bioassay, none of these compounds displayed obvious anti-inflammatory and cytotoxic effects.
ABSTRACT
Three new 11,20-epoxybriaranes-fragilides U-W (1-3), as well as two known metabolites, junceellonoid D (4) and junceellin (5), were obtained from the octocoral Junceella fragilis. The structures of briaranes 1-3 were elucidated by spectroscopic methods and briaranes 3 and 5 displayed inhibition effects on inducible nitric oxide synthase (iNOS) release from RAW264.7.
Subject(s)
Anthozoa/physiology , Diterpenes/metabolism , Animals , Cyclooxygenase 2/metabolism , Cyclooxygenase Inhibitors/pharmacology , Diterpenes/chemistry , Diterpenes/classification , Gene Expression Regulation, Enzymologic/drug effects , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Molecular Structure , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/metabolism , RAW 264.7 CellsABSTRACT
Three new 8-hydroxybriaranes-fragilides R-T (1-3) were obtained from a sea whip gorgonian coral Junceella fragilis. The structures of briaranes 1-3 were elucidated by using spectroscopic methods, including 1D (1H and 13C NMR), 2D (COSY, HSQC, HMBC, and NOESY experiments) NMR studies, and (+)-HRESIMS. Fragilides S and T (2 and 3) are the only briaranes known to possess 8α-hydroxy and 17ß-methyl groups, respectively. Briarane 2 exerted an inhibition effect on iNOS release from RAW264.7; a macrophage cell line that originated from a mouse monocyte macrophage, stimulated with lipopolysaccharides.
Subject(s)
Anthozoa/chemistry , Anti-Inflammatory Agents/pharmacology , Diterpenes/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Diterpenes/chemistry , Diterpenes/isolation & purification , Mice , Molecular Structure , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/metabolism , Proton Magnetic Resonance Spectroscopy , RAW 264.7 Cells , Structure-Activity RelationshipABSTRACT
: An Antarctic coral belonging to the order Pennatulacea, collected during the 2013 austral autumn by trawl from 662 to 944 m depth, has yielded three new briarane diterpenes, bathyptilone A-C (1-3) along with a trinorditerpene, enbepeanone A (4), which bears a new carbon skeleton. Structure elucidation was facilitated by one- and two-dimensional NMR spectroscopy, mass spectrometry and confirmed by X-ray crystallography. The three compounds were screened in four cancer cell lines. Bathyptilone A displayed selective nanomolar cytotoxicity against the neurogenic mammalian cell line Ntera-2.
Subject(s)
Anthozoa/chemistry , Terpenes/chemistry , Animals , Antarctic Regions , Crystallography, X-Ray/methods , Diterpenes/chemistry , HeLa Cells , Humans , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methodsABSTRACT
Two new 11,20-epoxybriaranes, fragilides P (1) and Q (2), as well as two known analogues, robustolide F (3) and juncin Z (4), were obtained from the gorgonian coral Junceella fragilis. The structures, including the absolute configurations of briaranes 1 and 2, were elucidated by using spectroscopic methods and comparing the spectroscopic and rotation data with those of known related analogues. Briarane 4 decreased the generation of superoxide anions by human neutrophils. The propionate group in 1 is rarely found.
Subject(s)
Anthozoa/chemistry , Diterpenes/chemistry , Plant Proteins/chemistry , Animals , Diterpenes/isolation & purification , Diterpenes/pharmacology , Models, Molecular , Molecular Conformation , Molecular Structure , Plant Proteins/isolation & purification , Plant Proteins/pharmacology , Spectrum AnalysisABSTRACT
The structures, names, bioactivities, and references of 82 natural products, including 48 new metabolites, purified from the gorgonian corals belonging to the genus Junceella are described in this review. All compounds mentioned in this review were obtained from Junceella fragilis, Junceella gemmacea, Junceella juncea, and Junceella sp., collected from tropical Indo-Pacific Ocean. Some of these compounds exhibited potential biomedical activities.
Subject(s)
Anthozoa/metabolism , Anti-Bacterial Agents/chemistry , Anti-Inflammatory Agents/chemistry , Antifungal Agents/chemistry , Biological Products/chemistry , Animals , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Biological Products/isolation & purification , Biological Products/metabolism , Molecular Structure , Pacific OceanABSTRACT
Two new briarane metabolitesfragilides K (1) and L (2)along with five known analoguesgemmacolide X, praelolide, juncins P and ZI, and gemmacolide V (3â»7)were extracted and purified from Junceella fragilis, a gorgonian coral. Based on data obtained via spectroscopic techniques, the structures of new briaranes 1 and 2 were determined and the cyclohexane rings in 1 and 2 were found to exist in chair and twist boat conformation, respectively. Additionally, anti-inflammatory analysis showed that briaranes 2, 3, and 6 inhibited pro-inflammatory inducible nitric oxide synthase protein expression and briaranes 3 and 7 suppressed the cyclooxygenase-2 level, in LPS-stimulated murine macrophage-like RAW264.7 cells.