Neopetromin, a Cyclic Tripeptide with a C-N Cross-Link, from the Marine Sponge Neopetrosia sp., That Causes Vacuole Fragmentation in Tobacco BY-2 Cells.

HPLC-MS analysis revealed the presence of an unreported peptide in the extract of the marine sponge Neopetrosia sp. Its structure was determined as a tripeptide, named neopetromin (1), composed of two tyrosine and one tryptophan residues with a heteroaromatic C-N cross-link between side chains. The absolute configuration of amino acids was determined using Marfey's method after ozonolysis and hydrolysis of 1. Compound 1 promoted vacuole fragmentation in an actin-independent manner in tobacco BY-2 cells.

Integration of LC/MS, NMR and Molecular Docking for Profiling of Bioactive Diterpenes from Euphorbia mauritanica L. with in Vitro Anti-SARS-CoV-2 Activity.

In spite of tremendous efforts exerted in the management of COVID-19, the absence of specific treatments and the prevalence of delayed and long-term complications termed post-COVID syndrome still urged all concerned researchers to develop a potent inhibitor of SARS-Cov-2. The hydromethanolic extracts of different parts of E. mauritanica were in vitro screened for anti-SARS-Cov-2 activity. Then, using an integrated strategy of LC/MS/MS, molecular networking and NMR, the chemical profile of the active extract was determined. To determine the optimum target for these compounds, docking experiments of the active extract's identified compounds were conducted at several viral targets. The leaves extract showed the best inhibitory effect with IC50 8.231±0.04 µg/ml. The jatrophane diterpenes were provisionally annotated as the primary metabolites of the bioactive leaves extract based on multiplex of LC/MS/MS, molecular network, and NMR. In silico studies revealed the potentiality of the compounds in the most active extract to 3CLpro, where compound 20 showed the best binding affinity. Further attention should be paid to the isolation of various jatrophane diterpenes from Euphorbia and evaluating their effects on SARS-Cov-2 and its molecular targets.

Glabratephrin reverses doxorubicin resistance in triple negative breast cancer by inhibiting P-glycoprotein.

Triple-negative breast cancer is one of the most aggressive breast cancer. The first therapeutic option is chemotherapy, often based on anthracycline as doxorubicin. However, chemotherapy efficacy is limited in by the presence of P-glycoprotein (Pgp), a membrane transporter protein that effluxes doxorubicin, reducing its cellular accumulation and toxicity. Inhibiting Pgp activity with effective and non-toxic products is still an open challenge. In this work, we demonstrated that the natural product Glabratephrin (Glab), a prenylated flavonoid from Tephrosia purpurea with a unique chemical structure, increased doxorubicin accumulation and cytotoxicity in triple negative breast cancer cells with high levels of Pgp, characterized by both acquired or intrinsic resistance to doxorubicin. Glab also reduced the growth of Pgp-expressing tumors, without adding significant extra-toxicities to doxorubicin treatment. Interestingly, Glab did not change the expression of Pgp, but it reduced the affinity for Pgp and the efflux of doxorubicin, as suggested by the increased Km and the reduced Vmax. In silico molecular docking predicted that Glab binds two residues (phenylalanine 322, glutamine 721) localized in the transmembrane domains of Pgp, facing the extracellular environment. Moreover, site-directed mutagenesis identified glycine 185 as a critical residue mediating the reduced catalytic efficacy of Pgp elicited by Glab. We propose Glab as an effective and safe compound able to reverse doxorubicin resistance mediated by Pgp in triple negative breast cancers, opening the way to a new combinatorial approach that may improve chemotherapy efficacy in the most refractory and aggressive breast cancer.

Cyclopsammocinamides A and B, Enantiomeric Cyclic Peptides of Cyclocinamide A, from the Marine Sponge Psammocinia sp.

LC-MS and molecular networking analyses of the extract of the marine sponge Psammocinia sp. indicated the presence of two new compounds with multiple halogens. LC-MS-guided isolation yielded cyclic peptides, cyclopsammocinamides A (1) and B (2), in an enantiomeric relationship to cyclocinamide A (3). Planar structures of 1 and 2 were elucidated by NMR and mass spectroscopic analyses and the absolute configurations of the amino acid residues were determined using Marfey's method with their acid hydrolysates. The sponge extract exhibited cytotoxicity and the bioassay-guided isolation afforded a dimeric dilactone macrolide, swinholide A, as the cytotoxic compound.

Taichunins E-T, Isopimarane Diterpenes and a 20-nor-Isopimarane, from Aspergillus taichungensis (IBT 19404): Structures and Inhibitory Effects on RANKL-Induced Formation of Multinuclear Osteoclasts.

Fifteen new isopimarane-type diterpenes, taichunins E-S (1-15), and a new 20-nor-isopimarane, taichunin T (16), together with four known compounds were isolated from Aspergillus taichungensis (IBT 19404). The structures of these new compounds were determined by NMR and mass spectroscopy, and their absolute configurations were analyzed by NOESY and TDDFT calculations of ECD spectra. Taichunins G, K, and N (3, 7, and 10) completely inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts in RAW264 cells at 5 µM, with 3 showing 92% inhibition at a concentration of 0.2 µM.

Halichonic Acid B, a Rearranged Nitrogenous Bisabolene-Type Sesquiterpene from a Marine Sponge Axinyssa sp.

A new rearranged nitrogenous bisabolone-type sesquiterpene, halichonic acid B (1), was isolated from a marine sponge Axinyssa sp. together with halichonic acid (2) and (6R,7S)-7-amino-7,8-dihydro-α-bisabolene (3). The structure of 1 was determined by extensive NMR and MS analyses, revealing an unprecedented carbon framework, and its absolute configuration was elucidated by time-dependent density-functional theory (TDDFT)-based electronic circular dichroism (ECD) spectrum calculation. We propose that 1 and 2 may be biosynthesized in the same pathway, involving the reaction between farnesyl pyrophosphate and glycine, followed by cyclization.

Enhanced Activity and Sustained Release of Protocatechuic Acid, a Natural Antibacterial Agent, from Hybrid Nanoformulations with Zinc Oxide Nanoparticles.

Hybrid nanostructures can be developed with inorganic nanoparticles (NPs) such as zinc oxide (ZnO) and natural antibacterials. ZnO NPs can also exert antibacterial effects, and we used them here to examine their dual action in combination with a natural antibacterial agent, protocatechuic acid (PCA). To produce hybrid nanoformulations, we functionalized ZnO NPs with four types of silane organic molecules and successfully linked them to PCA. Physicochemical assessment confirmed PCA content up to ~18% in hybrid nanoformulations, with a PCA entrapment efficiency of ~72%, indicating successful connection. We then investigated the in vitro release kinetics and antibacterial effects of the hybrid against Staphylococcus aureus. PCA release from hybrid nanoformulations varied with silane surface modification. Within 98 h, only 8% of the total encapsulated PCA was released, suggesting sustained long-term release. We used nanoformulation solutions collected at days 3, 5, and 7 by disc diffusion or log reduction to evaluate their antibacterial effect against S. aureus. The hybrid nanoformulation showed efficient antibacterial and bactericidal effects that also depended on the surface modification and at a lower minimum inhibition concentration compared with the separate components. A hybrid nanoformulation of the PCA prodrug and ZnO NPs offers effective sustained-release inhibition of S. aureus growth.

Chemical Constituents of the Vietnamese Marine Sponge Gelliodes sp. and Their Cytotoxic Activities.

A new decenoic acid derivative, gelliodesinic acid, and a naturally new alkaloid, together with three known furanoterpenoids and two known indole alkaloids, were isolated from the MeOH extract of the marine sponge Gelliodes sp. collected in Vietnam. The chemical structures of the isolated compounds were determined by analyses of 1D- and 2D-NMR and MS data and by comparisons of the data with those reported in the literature. The cytotoxicity assay against HeLa, MCF-7, and A549 cancer cell lines revealed that the three known furanoterpenes exhibited cytotoxic activities with IC50 values ranging from 23.6 to 75.5 µM against the three cell lines, and that 1H-indole-3-carboxylic acid showed cytotoxicity with an IC50 value of 89.2 µM against A549 cancer cell lines.

Tetradehydrohalicyclamine B, a new proteasome inhibitor from the marine sponge Acanthostrongylophora ingens.

A new halicyclamine derivative, tetradehydrohalicyclamine B (1), was isolated from the marine sponge Acanthostrongylophora ingens, along with halicyclamine B (2) as proteasome inhibitors. Compound 1 is the second example found to have a pyridinium ring in the halicyclamine family. Although the relative configuration of 2 was previously determined by X-ray crystallographic analysis, here we determined the absolute configuration of 2 by ECD experiment. Compounds 1 and 2 inhibited the constitutive proteasome as well as the immunoproteasome. The inhibitory activities of 2 were 4- to 10-fold more potent than those of 1.

Benzimidazole - Schiff bases and their complexes: synthesis, anticancer activity and molecular modeling as Aurora kinase inhibitor.

A new series of Schiff bases containing benzіmidazole moiety 11-17 were synthesized by the reaction of 4-(1H-benzо[d]іmіdazоl-2-yl)anіline (1) with different aromatic aldehydes (4-10) via conventional heating and microwave irradiation methods. The structures of the novel Schiff bases were characterized by using different spectral data. Also, metal complexes 18-21 of compound 13 were synthesized, and their structure was confirmed by spectral measurements (IR, NMR, UV), molar conductivity, magnetic susceptibility and thermo-gravimetric analysis. The novel synthesized ligand 13 and its complexes 18-21 were tested for their in vitro antitumor activities towards breast, liver and lung cancer cell lines. Also, the acute toxicity of the prepared compounds 13 and 18-21 was determined in vivo. The results showed that the newly synthesized compounds 13 and 18-21 exhibited a significant activity against cancer, especially for complex 21, compared to standard drug doxorubicin. The molecular docking of complexes 20 and 21 has been also studied as Aurora kinase inhibitors.

Sulawesins A-C, Furanosesterterpene Tetronic Acids That Inhibit USP7, from a Psammocinia sp. Marine Sponge.

Three new furanosesterterpene tetronic acids, sulawesins A-C (1-3), were isolated from a Psammocinia sp. marine sponge, along with the known compounds ircinins-1 (4) and -2 (5). Although ircinins-1 and -2 were previously isolated as (+)- or (-)-enantiomers from marine sponges, we isolated them as enantiomeric mixtures. Sulawesins A and B possess a new carbon skeleton with a 5-(furan-3-yl)-4-hydroxycyclopent-2-enone moiety and were also found to be diastereomeric mixtures of four isomers by an HPLC analysis with a chiral-phase column. Sulawesin C has a dimeric structure of ircinin-1 and is the first dimer in this family. USP7, a deubiquitinating enzyme, is an emergent target of cancer therapy, and the isolated compounds inhibited USP7 with IC50 values in the range of 2.7-4.6 µM.

Ceylonins A-F, Spongian Diterpene Derivatives That Inhibit RANKL-Induced Formation of Multinuclear Osteoclasts, from the Marine Sponge Spongia ceylonensis.

Six new spongian diterpene derivatives, ceylonins A-F (1-6), were isolated from the Indonesian marine sponge Spongia ceylonensis along with spongia-13(16),14-dien-19-oic acid (7). They contained three additional carbons in ring D to supply an ether-bridged bicyclic ring system. Their structures were elucidated by analyzing NMR spectroscopic data and calculated ECD spectra in comparison to experimental ECD spectra. The bicyclic ring system may be derived from the major metabolite 7 and a C3 unit (an acrylic acid equivalent) through an intermolecular Diels-Alder reaction, which was experimentally supported by the formation of 1-6 from 7 and acrylic acid. The inhibitory effects of the isolated compounds on the RANKL-induced formation of multinuclear osteoclasts in RAW264 macrophages were examined.

Ceylonamides A-F, Nitrogenous Spongian Diterpenes That Inhibit RANKL-Induced Osteoclastogenesis, from the Marine Sponge Spongia ceylonensis.

Seven new spongian diterpenes, ceylonamides A-F (1-6) and 15α,16-dimethoxyspongi-13-en-19-oic acid (7), were isolated from the Indonesian marine sponge Spongia ceylonensis along with eight known spongian diterpenes, 8-15. Compounds 1-6 were determined to be nitrogenous spongian diterpenes. The isolated compounds were examined for the inhibition of RANKL-induced osteoclastogenesis in RAW264 macrophages. Ceylonamide A (1) exhibited the most potent inhibitory activity with an IC50 value of 13 µM, followed by ceylonamide B (2) (IC50, 18 µM). An examination of the structure-activity relationships of the isolated compounds revealed that the position of the carbonyl group of the γ-lactam ring and bulkiness of the substituent at its nitrogen atom were important for inhibitory activity.

Halenaquinone inhibits RANKL-induced osteoclastogenesis.

Halenaquinone was isolated from the marine sponge Petrosia alfiani as an inhibitor of osteoclastogenic differentiation of murine RAW264 cells. It inhibited the RANKL (receptor activator of nuclear factor-κB ligand)-induced upregulation of TRAP (tartrate-resistant acid phosphatase) activity as well as the formation of multinuclear osteoclasts. In addition, halenaquinone substantially suppressed RANKL-induced IκB degradation and Akt phosphorylation. Thus, these results suggest that halenaquinone inhibits RANKL-induced osteoclastogenesis at least by suppressing the NF-κB and Akt signaling pathways.

Acantholactam and pre-neo-kauluamine, manzamine-related alkaloids from the Indonesian marine sponge Acanthostrongylophora ingens.

Two new manzamine alkaloids, acantholactam (3) and pre-neo-kauluamine (4), were isolated from the marine sponge Acanthostrongylophora ingens along with manzamine A (1) and neo-kauluamine (2). Acantholactam contains a γ-lactam ring N-substituted with a (Z)-2-hexenoic acid moiety and is proposed to be biosynthetically derived from manzamine A by oxidative cleavage of the eight-membered ring. Compound 4 was converted to the dimer 2 during storage, suggesting nonenzymatic dimer formation. Among the four isolated compounds, 1, 2, and 4 showed proteasome inhibitory activity.

A new linear peptide, higapeptin, isolated from the mud flat-derived fungus Acremonium persicinum inhibits mitochondrial energy metabolism.

A combination of LC-MS/MS and feature-based molecular networking analyses led to the isolation of a new adenopeptin analog, higapeptin (1), and four known peptides, adenopeptin (2), adenopeptins B and C (3 and 4), and acremopeptin (5), from the rice culture of the fungus Acremonium persicinum (18F04103) isolated from a mud flat of the Ariake Sea in Kyushu, Japan. The structure of 1 was determined by NMR and MS/MS fragmentation analyses. The absolute configuration of the constituent amino acids was determined by Marfey's analysis after acid hydrolysis. The C-terminal residue was synthesized, and its absolute configuration was established by Marfey's analysis. Compounds 1 and 2 were found to inhibit mitochondrial energy metabolism, similar to efrapeptin D (6), a known mitochondrial ATPase inhibitor.

An unusual 2-O-glyceryl-glycosyl-γ-pyrone from Erigeron annuus (L.) with potential antifungal activity: in-vitro and in-silico study.

Phytochemical characterisation of the polar fraction of Erigeron annuus extract led to the isolation of glycerylerigeroside (1), a unique γ-pyrone derivative. Structure of 1 was decided by intensive study of NMR and mass spectra as 3-O-[4'-((1,3-dihydroxypropan-2-yl)oxy)-ß-D-glucopyranoside)]-4H-pyran-4-one, with uncommon glyceroxy side chain attached to 4' position of pyromeconic acid ß-D-glucopyranoside. Antimicrobial potential of 1 was tested against Staphylococcus aureus, Salmonella enterica, and Candida albicans. Compound 1 strongly inhibited growth of Candida albicans (MIC = 17.24 µM/disc), compared to fluconazole (MIC = 16.33 µM/disc). Meanwhile, it moderately inhibited the growth of Staphylococcus aureus (MIC = 71.84 µM/disc) and Salmonella enterica (MIC = 71.84 µM/disc), as compared with thiophenicol (MIC = 14.05 µM/disc) and (MIC = 14.05 µM/disc), respectively. The binding mode of 1 with the active site of sterol 14α-demethylase (CYP51) from Candida albicans (PDB ID: 5TZ1), in combination with fluconazole, was predicted by molecular docking study and supported the antifungal activity.

epi-Magnolin, a tetrahydrofurofuranoid lignan from the oleo-gum resin of Commiphora wightii, as inhibitor of pancreatic cancer cell proliferation, in-vitro and in-silico study.

Five known furofuran lignans, dia-sesamin (1), 5-methoxysesamin (2), epi-magnolin (3), kobusin (4) and yangambin (5) were isolated for the first-time from the oleo-gum resin of Commiphora wightii. This is the first report on the 13C NMR assignments for epi-magnolin (3). Each of the isolated compounds was evaluated for its ability to inhibit MIA PaCa-2 pancreatic cancer cell line. Among them, epi-magnolin (3) displayed potential activity (IC50 = 29 nM) compared to colchicine (IC50 = 56 nM). 3D-flexible alignment revealed that epi-magnolin (3) has great matching with the tubulin polymerization inhibitor, colchicine. Meanwhile, docking studies exhibited that compounds 1-5 displayed good binding free energies against colchicine binding site (CBS) of tubulin with binding modes that were highly comparable to that of colchicine. Compounds 2, 3, and 5 showed superior binding free energies than colchicine (-24.37 kcal/mol). epi-Magnolin (3) showed the highest binding score against CBS. MD simulation studies confirmed the stability of epi-magnolin (3) in the active site for 200 ns. Furthermore, four online servers (Swiss ADME, pkCSM pharmacokinetics, AdmetSAR, and ProTox-II) were utilized to predict the ADMET parameters. The in-silico pharmacokinetics predictions reveled that epi-magnolin (3) has significant oral bioavailability and drug-like capabilities.Communicated by Ramaswamy H. Sarma.

Arteperoxides A-C, tris-normonoterpene-sesquiterpene conjugates with peroxide-bridges from Artemisia judaica exhibiting antiosteoclastogenic activity.

Antiosteoclastogenic-guided screening was conducted with 120 extracts of the medicinal plants collected in Egypt that led to the selection of Artemisia judaica L. (Asteraceae). Three undescribed davanone-related terpenoids, arteperoxides A-C, were isolated from the extract with two known derivatives, hydroxydavanone and davana acid. Structural analysis revealed that arteperoxides A-C were tris-normonoterpene-sesquiterpene conjugates with peroxide bridges. Although davanone derivatives with peroxides, such as a hydroperoxyl and peroxyhemiketal groups, have been isolated from Artemisia species, arteperoxides A-C are the first variations observed to contain peroxide bridges between two terpene-derived units. The absolute configurations of arteperoxides A and B were studied based on their spectroscopic data compared with those of the semisynthetic analogs that have ether linkages. The natural and synthetic compounds were tested for the antiosteoclastogenic activity, and arteperoxide C and hydroxydavanone were more potent than other compounds at 20 µM.