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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 IC 50 value of 5.57 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., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

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.

Five undescribed dolabellane-type diterpenoids (1-5), together with three related known ones (6-8), were isolated from the soft coral Clavularia viridis. Their structures and stereochemistry were elucidated by extensive spectroscopic analysis and NMR calculation with DP4+ probability analysis. The absolute configurations of 1 and 5 were unambiguously determined by X-ray crystallographic analysis. A plausible biosynthetic connection between undescribed compounds 1-5 was proposed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A new cembranolide, namely, sinupendunculide A (1), along with eight known related compounds (2-9), was isolated from the South China Sea Soft coral Sinularia pendunculata. The structure of sinupendunculide A (1) was established by extensive spectroscopic analysis and X-ray diffraction experiments. In a bioassay, anti-colorectal cancer (CRC) activity was performed, and the results showed that several compounds exhibited cytotoxicity against RKO cells, and a preliminary structure-activity relationship was analysed. Meanwhile, the most effective compound 7 was proven to increase reactive oxygen species levels, which promoted cell apoptosis and inhibited cell proliferation., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Natural product dimers have intriguing structural features and often have remarkable pharmacological activities. We report here two uncommon marine gorgonian-derived symmetric dimers, weizhouochrones A ( 1 ) and B ( 2 ), with indenone-derived monomers, that were isolated from the coral Anthogorgia ochracea collected from the South China Sea. These dimers are difficult targets for structure elucidation that solely relies upon conventional NMR data such as NOEs and J -couplings. Here, to explore the application of emerging methods on the structure elucidation of challenging molecules, we explored a number of different anisotropic and computational NMR approaches. The measurements of anisotropic NMR parameters of weizhouochrone A, including residual dipolar couplings (RDCs) and residual chemical shift anisotropy (RCSA), allowed us to successfully determine the planar structure and its relative configuration. This result was corroborated by a computational NMR analysis based on DP4+ probability and computer-assisted 3D structure elucidation (CASE-3D).

A new diterpenoid with an unusual capnosane skeleton, sinuhumilol A ( 1 ), alone with twelve known diverse compounds ( 2-13 ), were isolated from the South China Sea soft coral Sinularia humilis. Their structures and stereochemistry were elucidated by extensive spectroscopic analysis, quantum chemical calculations, and/or by the comparison of the spectroscopic data with those reported in the literature. In bioassay, compound 11 exhibited interesting specific cytotoxicity against the human colon adenocarcinoma cell line HT-29 with IC 50 value of 12.5  µ M.

Two new cladiellin-type diterpenoids ( 1 and 2 ) and four known related compounds 3 - 6 , were isolated from the South China Sea soft coral Cladiella krempfi . Compound 2 is the third example of cladiellins of an unusual peroxy group in the C-6 position in C. krempfi . The structures and absolute configurations of the new compounds were established by extensive spectroscopic analysis, X-ray diffraction, and/or chemical correlation. In bioassay, all the compounds were evaluated for cytotoxicity and epidermal growth factor receptor (EGFR) inhibitory activity. A molecular docking experiment was conducted to study the structure-activity relationship of cladiellin-type diterpenoids on EGFR inhibitory activity.

Chemical investigation of the Hainan soft coral Sinularia hirta resulted in the isolation and identification of a library of sixteen structurally diverse terpenoids, including a dinorditerpenoid with an uncommon 17,19-dinorxeniaphyllane skeleton, namely sinuhirtone A ( 7 ), six new xeniaphyllane-type diterpenoids ( 1 - 6 ), one new norxeniaphyllanoid ( 8 ), two new norcaryophyllene-type sesquiterpenoids ( 9 and 10 ), together with six known related compounds ( 11 - 16 ). Compounds 1 - 3 are three new furanone-containing xeniaphyllane-type diterpenoids. The structures of the new compounds, including their absolute configurations, were determined by extensive spectroscopic analysis and a series of quantum chemical calculations, including quantum mechanical-nuclear magnetic resonance (QM-NMR), time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD), and optical rotatory dispersion (ORD) methods. A plausible biosynthetic connection between new compounds 1 - 9 was also proposed. New compounds 2 - 4 , 7 , and 8 were evaluated for in vitro cytotoxicity against four cancer cell lines.

Three complex polyoxygenated diterpenoids possessing uncommon tetradecahydro-2,13:6,9-diepoxybenzo[10]annulene scaffold, namely ximaoornatins A-C ( 1 - 3 ), one new eunicellin-type diterpene, litophynin K ( 4 ), and a related known compound, litophynol B ( 5 ) were isolated from the South China Sea soft coral Sinularia ornata . The structures and absolute configurations of 1 - 4 were established by extensive spectroscopic analysis, X-ray diffraction analysis, and/or modified Mosher's method. A plausible biosynthetic relationship of 1 and its potential precursor 4 was proposed. In a bioassay, none of the isolated compounds showed obvious anti-inflammatory activity on LPS-induced TNF-α release in RAW264.7 macrophages and PTP1B inhibitory effects.

A novel diterpenoid, sinunanolobatone A ( 1 ), featuring an unprecedented bicyclo[13.1.0]pentadecane carbon framework, along with two new casbane diterpenoids ( 2 and 3 ), and five known related ones ( 4 - 8 ) were isolated from the Sanya soft coral Sinularia nanolobata . The structures of the new compounds were established by detailed spectroscopic analysis, X-ray diffraction analysis, chemical reactions, or a quantum chemical computation method. A plausible biosynthetic pathway of 1 was proposed. In bioassay, the novel compound 1 showed significant inhibitory activity against lipopolysaccharide (LPS) induced inflammation in BV-2 microglial cells.

A further systematically chemical investigation of the South China Sea soft coral Sinularia erecta led to the discovery of two rare casbane diterpenoids with an uncommon 8,10-peroxide bridge, sinuereperoxides B (1) and C (2), five new casbanes with other oxygenated patterns (3-7), and seven known casbanes (8-14). The structures and absolute configurations of 1-7 were established by extensive spectroscopic data analyses, X-ray diffraction analysis, and/or quantum chemical calculations. In bioassay, compounds 2, 7, 11 and 12 exhibited considerable anti-inflammatory activity by the inhibition of TNF-α release, with IC 50 values of 33.8 μM, 5 μM, 9.9 μM and 8 μM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A novel diterpenoid, sinueretone A ( 1 ), featuring an unprecedented tricyclo[12.1.0.0 5,9 ]pentadecane carbon framework, along with two new ( 2 and 3 ) and one known ( 4 ) casbane diterpenoids were isolated from the South China Sea soft coral Sinularia erecta . The structures of the new compounds, especially their absolute stereochemistry, were established by extensive spectroscopic analysis, various quantum chemical calculations, and/or X-ray diffraction analyses. A plausible biogenetic relationship of 1 - 4 was proposed, which gave an insight for future biomimetic synthesis of the novel compounds. In a bioassay, compounds 1 and 2 displayed interesting anti-inflammatory activity by the inhibition of lipopolysaccharide-induced tumor necrosis factor-α protein release.

A novel norditerpenoid, sinusiaetone A ( 1 ), featuring an uncommon bicyclo[11.3.0]hexadecane carbon skeleton, and four polyoxygenated cembranoids ( 2-5 ) were isolated from the Hainan soft coral Sinularia siaesensis . Their structures were established by spectroscopic analysis, X-ray diffraction, quantum chemical computational approaches, and/or a modified Mosher's method. A plausible biosynthetic pathway of 1 and its biogenetic relationship with 2-5 were proposed. New compounds 1-3 displayed an interesting inhibitory activity against lipopolysaccharide-induced inflammation in BV-2 microglial cells.

The chemical investigation of the South China Sea soft coral Sinularia humilis has resulted in the isolation of a library of diverse diterpenoids, including four new cembranoids, namely, humilisins A-D ( 1 - 4 ), two new uncommon diterpenoids possessing a tetradecahydrocyclopenta[3',4']cyclobuta[1',2':4,5]cyclonona[1,2- b ]oxirene ring system, namely, humilisins E and F ( 5 and 6 ), and eight known related compounds ( 7 - 14 ). Humilisin A ( 1 ) is the first cembranoid with an ether linkage between C-3 and C-7. The structures and absolute configurations of 1 - 8 were determined by extensive spectroscopic data analyses, chemical reactions, and a series of quantum chemical calculations including quantum mechanical-nuclear magnetic resonance (QM-NMR), time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD), and optical rotatory dispersion (ORD) methods. In bioassay, compound 6 displayed anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells.

Lobane-type diterpenoids are not frequently discovered from marine soft corals. In this paper, three new lobane type diterpenes, 13-methoxyloba-8,10,15(16),17(18)-tetraene (1), 8,10,13(15)Z,16E-lobatetraene (2) and 19-hydroxy-lobatetraene (3), and a new natural compound, 17,18-epoxyloba-16-acetoxy-8,10,13(15)-trien (4), co-occurring with a known related diterpenoid, 18-methoxyloba-8,10,13(15),16(17)-tetraene (5), were isolated from the South China Sea soft coral Sinularia polydactyla. The structures of new compounds were determined by extensive spectroscopic analysis and by comparison with those reported in the literature. In bioassay, all the isolates were inactive on antibacterial, PTP1B inhibitory, and immunological activities. This study increased the chemical diversity of marine diterpenoids., (Copyright © 2020 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Two new steroids, (22R,23S)-3β-hydroxy-23-methyl-17,20-epoxyergost-5-en-22-yl acetate and (22R,23S)-5-hydroperoxy-23-methyl-5α-17,20-epoxyergost-6-ene-3β,22-diol, were isolated from the South China Sea soft coral Lobophytum sp., together with two related known ones. The structures of all compounds were elucidated by extensive spectroscopic analysis and by comparing their spectral data with those previously reported. The structure of (22R,23S)-3β-hydroxy-23-methyl-17,20-epoxyergost-5-en-22-yl acetate was further confirmed through chemical correlation. All the isolates were evaluated for the in vitro inhibitory activity against NF-κB, a potential target for the treatment of cancer, and (22R,23S)-5-hydroperoxy-23-methyl-5α-17,20-epoxyergost-6-ene-3β,22-diol exhibited moderate inhibition activity with IC 50 value of 8.96 μg/mL., (© 2020 Wiley-VHCA AG, Zurich, Switzerland.)

The first and in-depth chemical investigation of the South China Sea soft coral Sinularia scabra has resulted to the isolation of a library of diverse cembrane type diterpenoids, including six new compounds, namely xiguscabrates A and B (1 and 2), xiguscabral A (3), xiguscabrols A and B (4 and 5), and 8-epi-xiguscabrol B (6), and twenty-seven known analogs (7-33). Their structures were elucidated by extensive spectroscopic analysis and by the comparison with literature data. In bioassay, several isolates exhibited inhibitory effects on the ConA-induced T lymphocytes and/or LPS-induced B lymphocytes proliferation. Among them, compound 24 showed considerable specific inhibition on B cell proliferation, with IC 50 value of 4.4 μM and selectivity index (SI) of 10.9. The structure-activity relationship (SAR) of the tested metabolites was analyzed, and the further mechanism study of the specific B-cell targeted immunosuppressive compound 24 on purified CD19 + B cells was also performed to uncover the effects on the function and maturity of B cells, including cytokines production, abnormal activation, antigen presenting capacity and plasma cells formation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Two novel polyoxygenated diterpenoids, klyflaccilides A ( 1 ) and B ( 2 ), featuring an uncommon 6/5/8/3 tetracyclic ring system, were isolated from the Hainan soft coral Klyxum flaccidum . Their structures were established by extensive spectroscopic analysis, X-ray diffraction analysis, and/or a quantum chemical computation method. A plausible biosynthetic relationship of 1 and 2 with their potential precursor 3 was further proposed. Compounds 1 and 3 exhibited moderate anti-inflammatory activity by the inhibition of LPS-induced TNF-α protein release.

Three new diterpenoids with an unusual capnosane skeleton named lobophytrols A-C (1-3) were isolated from the South China Sea soft coral Lobophytum sp. along with one known related diterpene, (11S,12S,1E,3E,7E)-11,12-epoxycembra-1,3,7-triene (7). Their structures were elucidated on the basis of spectroscopic analysis and by comparison with those reported in the literature., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A novel diterpenoid, sarcomililate A (1), possessing a previously undescribed tricyclo[11.3.0.0 2,16 ]hexadecane scaffold, along with two new cembranoids, sarcomililatols A and B (2 and 3), and two known related diterpenoids (4 and 5), was isolated from the Hainan soft coral Sarcophyton mililatensis. The complete chemical structure including absolute configuration (AC) of 1 was unambiguously determined by a combination of residual dipolar coupling (RDC)-based NMR analysis, TDDFT-ECD (ECD = electronic circular dichroism) calculation, and Snatzke's method. The AC of 1 was further confirmed by a comparison with 2, whose AC was determined by anomalous X-ray diffraction. A plausible biogenetic relationship of 1-3 was further proposed. All the reported compounds exhibited interesting inhibitory effects on the ConA-induced T lymphocytes and/or lipopolysaccharide (LPS)-induced B lymphocytes proliferation.

Different chemotypes of Sinularia flexibilis exist in the Hainan island. Thus, a collection of this soft coral from a location different from the one of our previous study afforded three novel cembranoid esters featuring a n-butyl alcohol moiety, a structural element rare in natural products of both terrestrial and marine origin. The structures of the new compounds were elucidated by detailed spectroscopic analysis and by the comparison of their spectroscopic data with those reported in the literature. In addition, the absolute stereochemistry of the previously reported diepoxycembrene (9) was first time determined by the X-ray diffraction analysis. In bioassays, compounds 6-8 exhibited strong anti-inflammatory effect with IC 50 values of 2.7, 4.7, and 4.2 μM, respectively, whereas compound 5 displayed cytotoxicity against several cancer cells with IC 50 values ranging from 8.9 to 27.4 μM. A preliminary structural-activity relationship (SAR) was also described., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Three new diterpenes, xishacorenes A-C, featuring an undescribed bicyclo[3.3.1]nonane nucleus bearing 1-vinyl and 13-[(E)-4-methylpenta-1,3-dien-1-yl] alkyl chains, and a related monocyclic known compound, were isolated from the Xisha soft coral Sinularia polydactyla. The structures of xishacorenes A-C, including their absolute configurations, were elucidated by extensive spectroscopic analysis and TDDFT ECD calculations. The new compounds exhibit an interesting dose-dependent promotion effect on the ConA-induced T lymphocyte proliferation. A plausible biosynthetic pathway of xishacorenes A-C is proposed.

Nine new bicyclic cembranoids, sarcophytrols M-U(1-9), were isolated from the South China Sea soft coral Sarcophyton trocheliophorum as minor components, along with one known related cembranoid 10. Their structures were elucidated by detailed spectroscopic analysis and chemical conversion. The chemical structures of these metabolites are characterized by the different patterns of the additional cyclization within the 14-member skeleton, which leading to the formation of furan, pyran, oxepane, and peroxyl rings, respectively. Among them, sarcophytrols R and S(6 and 7) share a rare decaryiol skeleton with an unusual C12/C15 cyclization. In addition, the absolute configurations of sarcophytrols M and T(1 and 8) were determined by the modified Mosher's method. The research of these new secondary metabolites provided a further understanding of the diversity of cyclized cembranoids from the title species.