Discovery of Oxidized p-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.

Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 µM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-ß1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 µM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.

p-Terphenyls as Anti-HSV-1/2 Agents from a Deep-Sea-Derived Penicillium sp.

Guided by Global Natural Products Social molecular networking, two p-terphenyl derivatives and one 4,5-diphenyl-2-pyrone analogue, peniterphenyls A-C (1-3), together with five known p-terphenyl derivatives (4-8) and sulochrin (9), were obtained from a deep-sea-derived Penicillium sp. SCSIO41030. Their structures were elucidated using extensive NMR spectroscopic and HRESIMS data and by comparing the information with literature data. Peniterphenyl B (2) represented the first reported natural product possessing a 4,5-diphenyl-substituted 2-pyrone derivative. The p-terphenyl derivatives displayed inhibitory activities against HSV-1/2 with EC50 values ranging from 1.4 ± 0.6 to 9.3 ± 3.7 µM in Vero cells, which showed that they possessed antiviral activities with low cytotoxicity, superior to the current clinical drug acyclovir (EC50 3.6 ± 0.7 µM). Peniterphenyl A (1) inhibited HSV-1/2 virus entry into cells and may block HSV-1/2 infection through direct interaction with virus envelope glycoprotein D to interfere with virus adsorption and membrane fusion, and thus differs from the nucleoside analogues such as acyclovir. Our study indicated peniterphenyl A (1) could be a promising lead compound against HSV-1/2.

Neuronal Modulators from the Coral-Associated Fungi Aspergillus candidus.

Three new p-terphenyl derivatives, named 4″-O-methyl-prenylterphenyllin B (1) and phenylcandilide A and B (17 and 18), and three new indole-diterpene alkaloids, asperindoles E-G (22-24), were isolated together with eighteen known analogues from the fungi Aspergillus candidus associated with the South China Sea gorgonian Junceela fragillis. The structures and absolute configurations of the new compounds were elucidated on the basis of spectroscopic analysis, and DFT/NMR and TDDFT/ECD calculations. In a primary cultured cortical neuronal network, the compounds 6, 9, 14, 17, 18 and 24 modulated spontaneous Ca2+ oscillations and 4-aminopyridine hyperexcited neuronal activity. A preliminary structure-activity relationship was discussed.

Polyhydroxy p-Terphenyls from a Mangrove Endophytic Fungus Aspergillus candidus LDJ-5.

Six undescribed polyhydroxy p-terphenyls, namely asperterphenyllins A-F, were isolated from an endophytic fungus Aspergillus candidus LDJ-5. Their structures were determined by NMR and MS data. Differing from the previously reported p-terphenyls, asperterphenyllin A represents the first p-terphenyl dimer connected by a C-C bond. Asperterphenyllin A displayed anti-influenza virus A (H1N1) activity and protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC50 values of 53 µM and 21 µM, respectively. The anti-influenza virus A (H1N1) activity and protein tyrosine phosphatase 1B (PTP1B) inhibitory activity of p-terphenyls are reported for the first time. Asperterphenyllin G exhibited cytotoxicity against nine cell lines with IC50 values ranging from 0.4 to 1.7 µM. Asperterphenyllin C showed antimicrobial activity against Proteus species with a MIC value of 19 µg/mL.

Antibacterial p-Terphenyl with a Rare 2,2'-Bithiazole Substructure and Related Compounds Isolated from the Marine-Derived Actinomycete Nocardiopsis sp. HDN154086.

Assisted by MS/MS-based molecular networking and X-ray diffraction analysis, five new p-terphenyl derivatives, namely, nocarterphenyls D-H (1-5), were obtained and characterized from the cultures of the marine sediment-derived actinomycete Nocardiopsis sp. HDN154086. The skeleton of nocarterphenyl D (1) was defined to possess a rare 2,2'-bithiazole scaffold, naturally occurring for the first time, and nocarterphenyls E-H (2-5) are p-terphenylquinones with unusual thioether linked fatty acid methyl ester substitutions. Compound 1 showed promising activity against multiple bacteria with MIC values ranging from 1.5 to 6.2 µM, and 2 exhibited notable antibacterial activity against MRSA which surpassed the positive control ciprofloxacin.

A new p-terphenyl derivative from the fruiting bodies of Sarcodon imbricatus (L.) P. Karst.

A new p-terphenyl, 2',3'-diacetoxy-4,5,5',6',4'',5''-hexahydroxy-p-terphenyl (1), along with 12 known compounds were isolated from the fruiting bodies of Sarcodon imbricatus (Bankeraceae). Their structures were confirmed on the basis of extensive spectroscopic analysis and comparison with the spectral data in the literature. Compound 1 exhibited weak cytotoxicity against colon cancer SW480 and leukemia HL-60 cell lines, with IC50 values of 55.02 ± 1.79 µM and 44.71 ± 2.15 µM, respectively.

Cytotoxic p-terphenyls from the deep-sea-derived Aspergillus candidus.

From the deep-sea-derived fungus Aspergillus candidus, one novel (1) and three known (2-4) p-terphenyl derivates were isolated. The structure of the new compound was established mainly on the basis of extensive analysis of 1D and 2D NMR data. All four isolates were tested for in vitro anti-food allergic and antitumor bioactivities. Compounds 3 and 4 showed potent antiproliferative effect against four cancer cells of Hela, Eca-109, Bel-7402, and PANC-1 with IC50 values ranging from 5.5 µM to 9.4 µM.

Cytotoxic p-Terphenyls from a Marine-Derived Nocardiopsis Species.

Three new p-terphenyl derivatives, nocarterphenyls A-C (1-3), along with three known analogues (4-6) were isolated from the marine-derived actinobacterial strain Nocardiopsis sp. OUCMDZ-4936. Their structures were elucidated on the basis of spectroscopic analysis and a single-crystal X-ray diffraction experiment. Compounds 1 and 2 possess a benzothiazole and benzothiazine moiety, respectively, which are rare in the skeleton of p-terphenyls. Nocarterphenyl A (1) showed potent cytotoxic activity against the HL60 and HCC1954 cancer cell lines with the IC50 values of 0.38 and 0.10 µM among 26 human cancer cell lines.

Cytotoxic, antimicrobial and antiviral secondary metabolites produced by the plant pathogenic fungus Cytospora sp. CCTU A309.

Chemical analysis of extracts from cultures of the plant pathogenic fungus Cytospora sp. strain CCTU A309 collected in Iran led to the isolation of two previously unreported heptanedioic acid derivatives namely (2R,3S) 2-hydroxy-3-phenyl-4-oxoheptanedioic acid (1) and (2S,3S) 2-hydroxy-3-phenyl-4-oxoheptanedioic acid (2) as diastereomers, four previously undescribed prenylated p-terphenyl quinones 3-6 in addition to five known metabolites. Their structures were elucidated on the basis of extensive spectroscopic analysis and high-resolution mass spectrometry. For metabolites 1 and 2, the absolute configurations at C-2 were deduced from comparison of the 1H NMR difference of their (S)- and (R)-phenylglycine methyl ester derivatives while the relative configurations were tentatively assigned by a J-based analysis and confirmed by comparison of 13C chemical shifts to literature data. The isolated compounds were tested for their cytotoxic, antimicrobial (including biofilm inhibition), antiviral, and nematicidal activities. While only moderate antimicrobial effects were observed, the terphenyl quinone derivatives 3-6 and leucomelone (10) exhibited significant cytotoxicity against the mouse fibroblast L929 and cervix carcinoma KB-3-1 cell lines with IC50 values ranging from 2.4 to 26 µg/mL. Furthermore, metabolites 4-6 showed interesting antiviral activity against hepatitis C virus (HCV).

Cytotoxic p-Terphenyls from the Endolichenic Fungus Floricola striata.

Eleven new p-terphenyls, floricolins K-U (1-11), together with 13 biosynthetically related known compounds (12-24) were isolated from an endolichenic fungus, Floricola striata. Their structures were elucidated by extensive spectroscopic analyses and single-crystal X-ray diffraction measurements. The newly isolated p-terphenyls inhibited the growth of A2780, MCF-7, and A549 cell lines. Further evaluation for the multidrug resistance (MDR) reversal activity of compound 5 revealed it enhanced the sensitivity of MCF-7/ADR cells toward adriamycin 39-fold at 10 µM through modulating P-glycoprotein-mediated drug exclusion.

Secondary Metabolites from the Root Rot Biocontrol Fungus Phlebiopsis gigantea.

Three cyclopentanoids (phlebiopsin A⁻C), one glycosylated p-terphenyl (methyl-terfestatin A), and o-orsellinaldehyde were isolated from the biocontrol fungus Phlebiopsis gigantea, and their structures were elucidated by 1D and 2D NMR spectroscopic analysis, as well as by LC-HRMS. The biological activity of the compounds against the root rot fungus Heterobasidion occidentale, as well as against Fusarium oxysporum and Penicillium canescens, was also investigated, but only o-orsellinaldehyde was found to have any antifungal activity in the concentration range tested.

Bis-Indolyl Benzenoids, Hydroxypyrrolidine Derivatives and Other Constituents from Cultures of the Marine Sponge-Associated Fungus Aspergillus candidus KUFA0062.

A previously unreported bis-indolyl benzenoid, candidusin D (2e) and a new hydroxypyrrolidine alkaloid, preussin C (5b) were isolated together with fourteen previously described compounds: palmitic acid, clionasterol, ergosterol 5,8-endoperoxides, chrysophanic acid (1a), emodin (1b), six bis-indolyl benzenoids including asterriquinol D dimethyl ether (2a), petromurin C (2b), kumbicin B (2c), kumbicin A (2d), 2″-oxoasterriquinol D methyl ether (3), kumbicin D (4), the hydroxypyrrolidine alkaloid preussin (5a), (3S, 6S)-3,6-dibenzylpiperazine-2,5-dione (6) and 4-(acetylamino) benzoic acid (7), from the cultures of the marine sponge-associated fungus Aspergillus candidus KUFA 0062. Compounds 1a, 2a-e, 3, 4, 5a-b, and 6 were tested for their antibacterial activity against Gram-positive and Gram-negative reference and multidrug-resistant strains isolated from the environment. Only 5a exhibited an inhibitory effect against S. aureus ATCC 29213 and E. faecalis ATCC29212 as well as both methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE) strains. Both 1a and 5a also reduced significant biofilm formation in E. coli ATCC 25922. Moreover, 2b and 5a revealed a synergistic effect with oxacillin against MRSA S. aureus 66/1 while 5a exhibited a strong synergistic effect with the antibiotic colistin against E. coli 1410/1. Compound 1a, 2a-e, 3, 4, 5a-b, and 6 were also tested, together with the crude extract, for cytotoxic effect against eight cancer cell lines: HepG2, HT29, HCT116, A549, A 375, MCF-7, U-251, and T98G. Except for 1a, 2a, 2d, 4, and 6, all the compounds showed cytotoxicity against all the cancer cell lines tested.

Novel p-terphenyl glycoside with a rare 2,6-dideoxyhexopyranose moiety from Actinomycete strain SF2911 that inhibits cancer cell migration.

In the course of our search for inhibitors of LPS-induced NO production from microbial strains, an ethyl acetate extract of Actinomycete SF2911, isolated from a soil sample collected in Okinawa Prefecture, Japan, showed the inhibitory activity. The active principle was purified and structure determination led to the isolation of one new compound. Since the structure belongs to the terfestatin family, we named it terfestatin D (1). It was found to inhibit cellular migration of breast carcinoma cells as well as NO production. We herein report the isolation, structure elucidation and biological activities of this new compound.

Terphenyl derivatives and drimane - Phathalide/isoindolinones from Hypoxylon fendleri BCC32408.

The genus Hypoxylon, a member of the family Xylariaceae, has been known to produce significant secondary metabolites in terms of chemical diversity. Moreover, the compounds isolated can also be used as chemotaxonomic characters for differentiation among the two sections, which are sect. Annulata and sect. Hypoxylon. In our continuing chemical screening programme for novel compounds, the crude extracts of H. fendleri BCC32408 gave significant chemical profiles in HPLC analyses. Thus, the chemical investigation of these crude extracts was then carried out. The investigation led to the isolation of ten previously undescribed compounds including three terphenylquinones (fendleryls A - C), one terphenyl (fendleryl D), and six novel drimane - phthalide-type lactone/isoindolinones derivatives (fendlerinines A - F) along with seven known compounds (2-O-methylatromentin, rickenyl E, atromentin, rickenyls C - D, (+)-ramulosin, and O-hydroxyphenyl acetic acid). The chemical structures were determined on the basis of spectroscopic analyses, including 1D, 2D NMR and high-resolution mass spectrometry, as well as chemical transformations. In addition, these isolated compounds were assessed for antimicrobial activity including antimalarial (against Plasmodium falciparum, K-1 strain), antifungal (against Candida albicans), antibacterial (against Bacillus cereus) activities. Cytotoxicity against both cancerous (KB, MCF-7, NCI-H187) and non-cancerous (Vero) cells of these compounds were also evaluated.

New p-terphenyls from the endophytic fungus Aspergillus sp. YXf3.

Five new p-terphenyls named prenylterphenyllin D (1), prenylterphenyllin E (2), 2'-O-methylprenylterphenyllin (3), 4-O-methylprenylterphenyllin (4) and 3'-O-methylterphenyllin (5) together with seven known compounds (6-12), were isolated from cultures of Aspergillus sp. YXf3. The structures of the new compounds were elucidated by extensive MS and NMR analyses. The NMR and MS data of 5 is reported for the first time, as its structure was listed in SciFinder Scholar with no associated reference. Compounds 6 and 7 were distinguished from each other on the basis of 2D NMR experiments. Compounds 1, 2, 3 and 8 showed antibacterial activities against X. oryzae pv. oryzicola Swings and E. amylovora with the same MIC values of 20µg/mL while 10 exhibited activities against E. amylovora with an MIC value of 10µg/mL.

Terphenyl Derivatives from Allantophomopsis lycopodina.

Three secondary fungal metabolites 1-3 with a benzo[b]naphtho[2,1-d]furan skeleton were isolated from submerged cultures of the ascomycete Allantophomopsis lycopodina. The NMR-based structure elucidation was challenging due to a low H/C ratio of only 0.64 and 0.68, respectively. NMR measurements in two different solvents and the use of NMR experiments such as HSQC-TOCSY and LR-HSQMBC proved to be helpful in this respect. The proposed structures obtained from the comprehensive analysis of the NMR data were verified by comparison of recorded and computed NMR chemical shifts from quantum chemical calculations of several constitutional isomers and were further analyzed with the aid of the DP4 and DP4+ probabilities.

p-Terphenyl Derivatives from the Endolichenic Fungus Floricola striata.

Ten new p-terphenyl derivatives, floricolins A-J (1-10), together with six known compounds (11-16), were isolated from the extract of the endolichenic fungus Floricola striata. Chemical structures of these compounds were elucidated using spectroscopic data (HRESIMS and NMR). Among them, 9 and 10 were enantiomeric mixtures, and their configurations were established by single-crystal X-ray diffraction analysis using Cu Kα radiation. Evaluation of the isolated compounds against Candida albicans revealed that the most active compound, 3 (MIC 8 µg/mL), exerted fungicidal action by destruction of the cell membrane.

Rickenyls A-E, antioxidative terphenyls from the fungus Hypoxylon rickii (Xylariaceae, Ascomycota).

Our screening efforts for new natural products with interesting bioactivity have revealed the neotropical ascomycete Hypoxylon rickii as a prolific source. We isolated five secondary metabolites with a p-terphenyl backbone from the mycelial extract of a fermentation of this fungus in 70 l scale by using RP-HPLC, which were named rickenyls A-E (1-5). Their structures were elucidated by X-ray crystallography and NMR spectroscopy, complemented by HRESIMS. Two of the compounds contained a quinone core structure in ortho (2) and para-position (5), respectively. We obtained 2 spontaneously and by lead tetraacetate oxidation from 1. All compounds were screened for antimicrobial, antioxidative and cytotoxic activities. Rickenyl A (1) exhibited strong antioxidative effects and moderate cytotoxic activity against various cancer cell lines.

New metabolites from endolichenic fungus Pleosporales sp.

Eight new metabolites were obtained from the culture of an endolichenic fungus, Pleosporales sp. Their structures were determined as three terphenyl derivatives, cucurbitarins A-C (1-3, resp.), two structurally related compounds, cucurbitarins D and E (4 and 5, resp.), two benzocoumarins, 3,10-dihydroxy-4,8-dimethoxy-6-methylbenzocoumarin (6) and 3,8,10-trihydroxy-4-methoxy-6-methylbenzocoumarin (7), as well as one cyclohexenone, (5R)-5-hydroxy-2,3-dimethylcyclohex-2-en-1-one (8), based on the spectroscopic data.