Isolation and absolute configuration of alkylpyridine alkaloids from the marine sponge Hippospongia lachne.

Marine sponges are well known as prolific producers of structurally diverse molecules with valuable pharmacological potential. As part of our ongoing program to discover bioactive compounds from marine sponges collected from the Xisha Islands in the South China Sea, a chemical study on the specimens of Hippospongia lachne was conducted. As a result, eight undescribed compounds, including four zwitterionic alkylpyridinium salts, hippospondines A-D (1-4), and four 3-alkylpyridine alkaloids, hippospondines E (5), F (6), and (±)-hippospondine G (7), were isolated from the marine sponge H. lachne, together with one known 3-alkylpyridine alkaloid (8). The undescribed structures were elucidated by HRESIMS, NMR, DP4+ and CP3 probability analysis, and the Snatzke's method. Hippospondines A-D (1-4) represent the rare example of inner salt type alkylpyridinium alkaloid with a farnesyl moiety. Compounds 1-3 and 8 were subjected to cytotoxic and lymphocyte proliferation assays. Compound 3 exhibited a weak promotion effect on the ConA-induced T lymphocyte proliferation.

Arenarialins A-F, Anti-inflammatory Meroterpenoids with Rearranged Skeletons from the Marine Sponge Dysidea arenaria.

Six new sesquiterpene quinone/hydroquinone meroterpenoids, arenarialins A-F (1-6), were isolated from the marine sponge Dysidea arenaria collected from the South China Sea. Their chemical structures and absolute configurations were determined by HRMS and NMR data analyses coupled with DP4+ and ECD calculations. Arenarialin A (1) features an unprecedented tetracyclic 6/6/5/6 carbon skeleton, whereas arenarialins B-D (2-4) possess two rare secomeroterpene scaffolds. Arenarialins A-F showed inhibitory activity on the production of inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages with arenarialin D regulating the NF-κB/MAPK signaling pathway.

Dysambiol, an Anti-inflammatory Secomeroterpenoid from a Dysidea sp. Marine Sponge.

An unusual secomeroterpenoid, dysambiol (1), was isolated from a Dysidea sp. marine sponge collected from the South China Sea. Dysambiol features an unprecedented secomeroterpene scaffold with a rare lactone bridge. The structure of 1 was determined by extensive spectroscopic analysis, Mosher's method, and electronic circular dichroism calculation. Dysambiol displayed potent anti-inflammatory activity in LPS-induced Raw 264.7 macrophages by regulating the NF-κB/MPAK signaling pathway.

Aspergetherins A-D, New Chlorinated Biphenyls with anti-MRSA Activity from the Marine Sponge Symbiotic Fungus Aspergillus terreus 164018.

Aspergetherins A-D (1-4), four new chlorinated biphenyls, were isolated from the rice fermentation of a marine sponge symbiotic fungus Aspergillus terreus 164018, along with seven known biphenyl derivatives (5-11). The structures of four new compounds were determined by a comprehensive analysis of the spectroscopic data, including HR-ESI-MS and 2D NMR data. All 11 isolates were evaluated for their anti-bacterial activity against two strains of methicillin-resistant Staphylococcus aureus (MRSA). Among them, compounds 1, 3, 8 and 10 showed anti-MRSA activity with MIC values of 1.0-128 µg/mL. Preliminary structure-activity relationship analysis unveiled that both chlorinated substitution and esterification of 2-carboxylic acid could impact the antibacterial activity of biphenyls.

A Series of New Pyrrole Alkaloids with ALR2 Inhibitory Activities from the Sponge Stylissa massa.

Twelve new and four known alkaloids including five different structural scaffolds were isolated from the sponge Stylissa massa collected in the South China Sea. Compound 1 is the first identified precursor metabolite of the classic 5/7/5 tricyclic skeleton with unesterified guanidine and carboxyl groups, compounds 2-5 and 13-15 belong to the spongiacidin-type pyrrole imidazole alkaloids (PIAs). Z- and E-configurations of the spongiacidin-type PIAs often appeared concomitantly and were distinguished by the chemical shift analysis of 13C NMR spectra. The structures of all twelve new compounds were determined by NMR, MS, and ECD analysis combined with single-crystal data of compounds 1, 5, and 10. In the aldose reductase (ALR2) inhibitory assay, six 5/7/5 tricyclic compounds (2-5, 13-15) displayed significant activities. Compounds 13 and 14, as the representative members of spongiacidin-PIAs, demonstrated their ALR2-targeted activities in SPR experiments with KD values of 12.5 and 6.9 µM, respectively.

New Spiro-Sesquiterpenoids from the Marine Sponge Myrmekioderma sp.

Three new spiro-sesquiterpenoids, myrmekiones A-C (1-3), were isolated from the marine sponge Myrmekioderma sp. collected from the South China Sea. The structures of 1-3 were experimentally illuminated though comprehensive NMR spectra, X-ray diffraction analysis and calculated ECD. These three compounds possessed a special spiro skeleton. Compound 1 was characterized by a chamigrane-type structure, it is the first time to obtain the single-crystal of this type of oil compounds. 2 and 3 were a pair of diastereoisomers that possessed an acorane skeleton. This study expands the chemical diversity of marine origin spiro-metabolites.

Guaiane sesquiterpenes from the gorgonian Echinogorgia flora collected in the South China Sea.

Echinoflorine (1), a new dimethylamino-substituted guaipyridine alkaloid with a novel γ-lactone-cyclohepta[c]pyridine fused skeleton, and three new guaiane sesquiterpene lactones, echinofloranolides A-C (2-4), together with eight known guaiane sesquiterpenes were isolated from the gorgonian Echinogorgia flora collected in the South China Sea. Their structures were elucidated by 1D and 2D NMR, HRESIMS, calculated ECD and DP4+ probability analyses.

Dolabellane Diterpenes and Elemane Alkaloids from the Soft Coral Clavularia inflata Collected in the South China Sea.

Five new dolabellane diterpenes, clavularinlides A-E (1-5), and four new racemic elemane alkaloids, clavulacylides A-D (7-10), together with one known compound (6), were isolated from the soft coral Clavularia inflata collected in the South China Sea. Their structures were elucidated by 1D and 2D NMR, HRESIMS, calculated ECD, and DP4+ probability analyses. Compounds 1-7 showed anti-inflammatory activity in the zebrafish assay.

Lemnalemnanes A-C, Three Rare Rearranged Sesquiterpenoids from the Soft Corals Paralemnalia thyrsoides and Lemnalia sp.

Three novel sesquiterpenoids, lemnalemnanes A-C (1-3), were obtained from marine soft corals Paralemnalia thyrsoides and Lemnalia sp. Their structures were determined by 1D/2D NMR spectroscopy, HRESIMS, single-crystal X-ray diffraction analysis (Cu Kα), Mosher's method, and ECD quantum chemistry calculations. Lemnalemnane A (1) possessed an intriguing basket-like structure with a spiro[bicyclo[3.3.1]nonane-furan core, while lemnalemnanes B (2) and C (3) exhibited unusual 6/6/5 and 6/5/5 carbon skeletons, respectively. In the proposed biosynthesis pathway, 1-3 were suspected to originate from the same precursor, 4-O-deacetylparalemnolin D (4), a compound coisolated from both aforementioned species. Furthermore, lemnalemnane C (3) exhibited strong in vivo promoting-angiogenesis activity.

Lemnardosinanes A-I: New Bioactive Sesquiterpenoids from Soft Coral Lemnalia sp.

Two rearranged nardosinane sesquiterpenoids with novel carbon skeletons, lemnardosinanes A (1) and B (2), and seven new nardosinane-related sesquiterpeniod lemnardosinanes C-I (3-9), together with a known compound 6,7-seco-13-nornardosinan (10), were isolated from the soft coral Lemnalia sp. collected from Xisha Islands of the South China Sea. Their structures were elucidated by comprehensive spectroscopic analyses, Mosher's method, Mo2(OAc)4-induced circular dichroism experiment, and quantum chemical calculations. Plausible biosynthetic pathways of 1-10 were proposed. Compounds 1 and 10 displayed in vivo angiogenesis promoting activity in a zebrafish model. Compounds 3 and 4 exhibited antiviral activity against the H1N1 virus with IC50 values of 10.9 and 41.5 µM, respectively.

Cytotoxic Manoalide-Type Sesterterpenes from the Sponge Luffariella variabilis Collected in the South China Sea.

Thirteen new linear terpenes, including 11 rare acyclic manoalide derivatives (1-11), one polyprenylphenol derivative (12), and one polyprenylbenzaldehyde derivative (13), together with three known compounds (14-16) were isolated from the sponge Luffariella variabilis collected in the South China Sea. The planar structures were resolved by NMR and MS analyses, while the absolute configurations were fully elucidated by NOESY experiments, combined with experimental and calculated ECD spectra, acetal formation, empirical rules of 1H and 13C NMR shifts, DP4+ probability analyses, and Mosher's method. Compounds 1-7, 10, and 13 demonstrated cytotoxic activities against several human cancer cell lines with IC50 values ranging from 2 to 10 µM.

Terpenoids from the South China Sea soft coral Sinularia multiflora.

A rare sinulariane-type norcembranoid sinulariadiolide B (1) with a unique cyano group, and a eunicellin-based diterpenoid multifloralin (2), along with two known related analogues, sinulariadiolide (3) and sclerophytin E (4), were isolated from the extract of the South China Sea soft coral Sinularia multiflora. Their structures were elucidated on the basis of detailed spectroscopic analysis and by comparison with previously reported data. Compounds 2 and 4 showed potent antifouling activity against barnacle Balanus albicostatus.

Cytotoxic sesquiterpenoid quinones from South China Sea sponge Dysidea sp.

A new sesquiterpene, (+)-19-methylaminoavarone (1), together with six known compounds (2-7), were isolated from the Xisha Islands marine sponge Dysidea sp. The structures were elucidated based on their spectroscopic data. We revised the carbon spectrum data of the compound 2. The absolute configurations of compounds 1 and 2 were further confirmed by electronic circular dichroism (ECD) analysis. Compounds 1-3 and 5-7 showed potent cytotoxic activity against several human cancer cell lines.

Sesquiterpenoids from the soft coral Lemnalia sp.

Two new neolemnane-type sesquiterpenoids lemnolins A (1) and B (2), together with one known tricyclic sesquiterpenoid (3) were isolated from the South China Sea soft coral Lemnalia sp. The structures were elucidated by comprehensive spectroscopic analysis and ECD analysis. Compound 1 displayed antiviral activity against influenza A (H1N1) virus in vitro.

Isolation and Identification of Three New Sterigmatocystin Derivatives from the Fungus Aspergillus versicolor Guided by Molecular Networking Approach.

Molecular networking approach was applied for the targeted isolation of new sterigmatocystin derivatives, sterigmatocystins A-C, from the marine sponge-derived fungus Aspergillus versicolor. Sterigmatocystin A features a rare 6/6/6/6/5 polycyclic system. The structures of sterigmatocystins A-C, including absolute configurations, were determined on the basis of spectroscopic data and ECD calculations. Sterigmatocystin A showed more stronger promoting angiogenesis activity than the positive control at 1.25 µM level in transgenic fluorescent zebrafish. Sterigmatocystins A-C also exhibited moderate antiviral activity by the inhibition of HSV-2.

Clavukoellians G-K, New Nardosinane and Aristolane Sesquiterpenoids with Angiogenesis Promoting Activity from the Marine Soft Coral Lemnalia sp.

The chemical examination of the marine soft coral Lemnalia sp., collected at the Xisha islands in the South China Sea, resulted in the isolation of four new nardosinane-type sesquiterpenoids, namely clavukoellians G-J (1-4), and one new aristolane sesquiterpene, namely clavukoellian K (5), together with five known compounds, 6-10. The structure elucidation of the isolated natural products was based on various spectroscopic techniques including HRESIMS and NMR, while their absolute configurations were resolved on the basis of comparisons of the ECD spectra with the calculated ECD data. The isolated new compounds 1-5 were evaluated for their anti- and pro- angiogenesis activities in a transgenic fluorescent zebrafish (Tg(vegfr2:GFP)) model. Quantitative analysis revealed that compound 5 displayed pro-angiogenesis activity in a PTK787-induced vascular injury zebrafish model at 2.5 µM. Data showed that compound 5 significantly promoted the angiogenesis in a dose-dependent manner.

Bishomoscalarane Sesterterpenoids from the Sponge Dysidea granulosa Collected in the South China Sea.

Granulosane A (1), a new C27 bishomoscalarane sesterterpenoid with a rare 6/6/6/8 tetracyclic skeleton, together with eight additional new C27 bishomoscalarane sesterterpenes (2, 8-14) and five new C26 20,24-bishomo-25-norscalarane sesterterpenes (3-7), were isolated from the marine sponge Dysidea granulosa collected in the South China Sea. Their structures were elucidated by extensive spectroscopic analysis and quantum chemical calculation methods. Compound 4 showed antiproliferative activities against two cancer cell lines.

Two new compounds from the marine sponge derived fungus Penicillium chrysogenum.

Two new compounds (1 and 2) were isolated from the marine sponge derived fungus Penicillium chrysogenum by using various column chromatography techniques. Their structures were elucidated by extensive analysis of spectroscopic data and quantum chemical calculation. Compound 1 exhibited moderate activity against PTP1B with 2.95 ± 0.97% at the concentration of 30 µmol·L-1.

Agelanemoechine, a Dimeric Bromopyrrole Alkaloid with a Pro-Angiogenic Effect from the South China Sea Sponge Agelas nemoechinata.

One new dimeric bromopyrrole alkaloid, agelanemoechine, with an unprecedented imidazo [1,5-a] azepin nucleus together with one known dimeric bromopyrrole alkaloid sceptrin were isolated from the marine sponge Agelas nemoechinata. The structure elucidation and absolute configuration assignments were determined by extensive spectroscopic analyses and the comparison of experimental and calculated ECD. Agelanemoechine showed strong pro-angiogenic activity in zebrafish.

Combinational protective therapy for spinal cord injury medicated by sialic acid-driven and polyethylene glycol based micelles.

Spinal cord injury (SCI) leads to immediate disruption of neuronal membranes and loss of neurons, followed by extensive secondary injury process. Treatment of SCI still remains a tremendous challenge clinically. Minocycline could target comprehensive secondary injury via anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms. Polyethylene glycol (PEG), a known sealing agent, is able to seal the damaged cell membranes and reduce calcium influx, thereby exerting neuroprotective capacity. Here, an E-selectin-targeting sialic acid - polyethylene glycol - poly (lactic-co-glycolic acid) (SAPP) copolymer was designed for delivering hydrophobic minocycline to achieve combinational therapy of SCI. The obtained SAPP copolymer could self-assemble into micelles with critical micelle concentration being of 13.40 µg/mL, and effectively encapsulate hydrophobic minocycline. The prepared drug-loaded micelles (SAPPM) displayed sustained drug release over 72 h, which could stop microglia activation and exhibited excellent neuroprotective capacity in vitro. The SAPP micelles were efficiently accumulated in the lesion site of SCI rats via the specific binding between sialic acid and E-selectin. Due to the targeting distribution and combinational effect between PEG and minocycline, SAPPM could obviously reduce the area of lesion cavity, and realize more survival of axons and myelin sheaths from the injury, thus distinctly improving hindlimb functional recovery of SCI rats and conferring superior therapeutic effect in coparison with other groups. Our work presented an effective and safe strategy for SCI targeting therapy. Besides, neuroprotective capacity of PEG deserves further investigation on other central nervous system diseases.