P-terphenyl Derivatives Research Articles

P-Terphenyl and Orsellinic Acid Derivatives from the European Polyporales Terana coerulea and Sparassis brevipes.

Investigation of the secondary metabolites of the solid-state rice cultures from the European basidiomycetes Terana coerulea and Sparassis brevipes afforded three previously undescribed secondary metabolites identified as two p-terphenyl derivatives (1 and 2) and one orsellinic acid congener (3) in addition to another known, isoeverninic acid (4). Chemical structures of the isolated compounds were elucidated through comprehensive 1D and 2D NMR spectroscopic analyses, coupled with HR-MS and other spectral methods. The isolated compounds were assessed for their cytotoxic and antimicrobial activities. Compound 1 revealed weak antimicrobial properties, whereas the inseparable mixture of 3 and 4 featured moderate cytotoxic and antimicrobial effects.

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-β1-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-Terphenyl and Diphenyl Ether Derivatives from the Marine-Derived Fungus Aspergillus candidus HM5-4.

Two undescribed p-terphenyl derivatives, asperterphenylcins A-B (1-2), and two undescribed diphenyl ether derivatives, asperdiphenylcins A-B (3-4), together with three previously described p-terphenyl derivatives-4″-deoxyterprenin (5), terphenyllin (6), and 3″-hydroxyterphenyllin (7)-were obtained from the solid-rice culture of the marine-derived fungus Aspergillus candidus HM5-4, which was isolated from sponges from the South China Sea. Their structures were elucidated by HRESIMS data and NMR spectroscopic analysis. Compound 1 showed a strong inhibitory effect on Neoscytalidium dimidiatum, with an inhibition circle diameter of 31.67 ± 2.36 mm at a concentration of 10.0 µg/disc. Compounds 5 and 7 displayed cytotoxic activity against human chronic myeloid leukemia cells (K562), human liver cancer cells (BEL-7402), human gastric cancer cells (SGC-7901), human non-small cell lung cancer cells (A549) and human HeLa cervical cancer cells, with IC50 values ranging from 3.32 to 60.36 µM, respectively. Compounds 2, 6 and 7 showed potent inhibitory activity against α-glucosidase, with IC50 values of 1.26 ± 0.19, 2.16 ± 0.44 and 13.22 ± 0.55 µM, respectively.

Biosynthesis of p-Terphenyls in Aspergillus ustus Implies Enzymatic Reductive Dehydration and Spontaneous Dibenzofuran Formation.

p-Terphenyls contain a central benzene ring substituted with two phenyl residues at its para positions. Heterologous expression of a biosynthetic gene cluster from Aspergillus ustus led to the formation of four new p-terphenyl derivatives. Gene deletion experiments proved the formation and reductive dehydration of the terphenylquinone atromentin, followed by O-methylation and prenylation. Spontaneous dibenzofuran formation led to the final products. These results provide new insights into the biosynthesis of p-terphenyls in fungi and dibenzofuran formation in the biosynthesis of numerous natural products.

Structural tailoring of p-terphenyl scaffold: Towards advanced plastic scintillator

A comprehensive series of fifteen p-terphenyl derivatives has been designed and prepared using facile synthetic approaches (Suzuki-Miyaura and Friedel-Crafts reactions). Various alkyl, alkoxy or trifluoromethyl groups have been attached to p-terphenyl to gain both symmetrical and unsymmetrical derivatives. Symmetry breaking accounts for improved solubility of mono-substituted derivatives. Thermal analysis revealed a reversible formation of several crystalline phases and very high thermal robustness. Reduction and oxidation of the parent p-terphenyl π-system affected by the electronic and steric effects of the substituents were recorded by cyclic voltammetry. When compared to parent p-terphenyl, a narrowed HOMO–LUMO gap has been measured/calculated for most of the prepared derivatives. The absorption and emission maxima ranged from 286 to 293 and 341–360 nm, respectively. The latter is affected by the substitution more significantly, the fluorescence quantum yields are within the range of 0.52–0.75. Stokes shifts up to 6400 cm−1 were measured pointing to a large structural rearrangement (planarization) upon excitation. PTP derivatives were further used as primary and secondary luminophores for scintillation. 4-Methyl-p-terphenyl proved to be a superior luminophore with a straightforward synthesis, easy isolation, large solubility and excellent luminescence characteristic. Based on this derivative, a plastic scintillator has been manufactured that showed superior performance as compared to standard and widely used unsubstituted p-terphenyl. Thus, a relatively minor structural change (appending single methyl group) altered scintillation properties significantly.

Antiproliferative p-terphenyl derivatives isolated from the fungus Sarcodon scabripes

The ethanol extract of the fungus Sarcodon scabripes collected from north-central British Columbia, Canada, showed strong antiproliferative activity. Bioassay-guided purification using liquid-liquid extraction and Sephadex LH-20 size-exclusion chromatography, followed by HPLC-MS and 1D/2D NMR analyses, led to the isolation of five known compounds; four p-terphenyl (1-4) derivatives and one phenolic aldehyde (5). Compounds 1, 4, and 5 were isolated for the first time from the Sarcodon genus. The cytotoxicity MTT assay showed that compounds 1-5 have antiproliferative activity against human cervical cancer cells (HeLa). For compounds 1-4, this is the first report of their antiproliferative activity against cancer cells. For compound 2, this is the first report on its bioactivity. To our knowledge, this is the first description of the isolation of bioactive constituents from S. scabripes.

Structurally various p-terphenyls with neuraminidase inhibitory from a sponge derived fungus Aspergillus sp. SCSIO41315

Guided by Global Natural Products Social molecular networking, 14 new p-terphenyl derivatives, asperterphenyls A–N (1–14), together with 20 known p-terphenyl derivatives (15–34), were obtained from a sponge derived fungus Aspergillus sp. SCSIO41315. Among them, new compounds 2–8 and 15–17 were ten pairs of enantiomers. Comprehensive methods such as chiral-phase HPLC analysis, ECD calculations and X-ray diffraction analysis were applied to determine the absolute configurations. Asperterphenyls B (2) and C (3) represented the first reported natural p-terphenyl derivatives possessing a dicarboxylic acid system. Asperterphenyl A (1) displayed neuraminidase inhibitory activity with an IC50 value of 1.77 ± 0.53 µM and could efficiently inhibit infection of multiple strains of H1N1 with IC50 values from 0.67 ± 0.28 to 1.48 ± 0.60 µM through decreasing viral plaque formation in a dose-dependent manner, which suggested that asperterphenyl A (1) might be exploited as a potential antiviral compound in the pharmaceutical fields.

P-Terphenyl glucosides from the culture broth of Phlebiopsis castanea.

A new p-terphenyl derivative, hydroxystrepantibin D (1), was isolated along with two known p-terphenyls (2 and 3) from the culture broth of Phlebiopsis castanea. These compounds were isolated using silica gel column chromatography, reversed-phase medium-pressure liquid chromatography, Sephadex LH-20 column chromatography, and preparative HPLC. Their structures were determined based on spectroscopic methods. These compounds exhibited free radical scavenging activities with IC50 values in the range from 22.2 to 158.4 μM against 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical and in the range from 161.1 to 356.1 μM against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical.

Discovery of p-Terphenyl Metabolites as Potential Phosphodiesterase PDE4D Inhibitors from the Coral-Associated Fungus Aspergillus sp. ITBBc1.

Chemical investigation of the fermentation extract of the coral-associated fungus Aspergillus sp. ITBBc1 led to the discovery of five unreported p-terphenyl derivatives, sanshamycins A-E (1-5), together with five previously described analogues, terphenyllin (6), 3-hydroxyterphenyllin (7), candidusin A (8), 4,5-dimethoxycandidusin A (9), and candidusin C (10). Their structures were elucidated by HRESIMS data and NMR spectroscopic analysis. Compound 1 represents the first example of p-terphenyls with an aldehyde substitution on the benzene ring. Compounds 2-4 feature varying methoxyl and isopentenyl substitutions, while compound 5 features a five-membered lactone linked to a biphenyl. These findings expand the chemical diversity of the family of p-terphenyl natural products. Compounds 1-6 and 9 were evaluated for their inhibitory activity against type 4 phosphodiesterase (PDE4), which is a fascinating drug target for treatment of inflammatory, respiratory, and neurological diseases. Compound 3 was the most potent and exhibited PDE4D inhibitory activity with an IC50 value of 5.543 µM.

Binding of Vialinin A and p-Terphenyl Derivatives to Ubiquitin-Specific Protease 4 (USP4): A Molecular Docking Study.

The para-terphenyl derivative vialinin A (Vi-A), isolated from Thelephora fungi, has been characterized as a potent inhibitor of the ubiquitin-specific protease 4 (USP4). Blockade of USP4 contributes to the anti-inflammatory and anticancer properties of the natural product. We have investigated the interaction of Vi-A with USP4 by molecular modeling, to locate the binding site (around residue V98 within the domain in USP segment) and to identify the binding process and interaction contacts. From this model, a series of 32 p-terphenyl compounds were tested as potential USP4 binders, mainly in the vialinin, terrestrin and telephantin series. We identified 11 compounds presenting a satisfactory USP4 binding capacity, including two fungal products, vialinin B and aurantiotinin A, with a more favorable empirical energy of USP4 interaction (ΔE) than the reference product Vi-A. The rare p-terphenyl aurantiotinin A, isolated from the basidiomycete T. aurantiotincta, emerged as a remarkable USP4 binder. Structure-binding relationships have been identified and discussed, to guide the future design of USP4 inhibitors based on the p-terphenyl skeleton. The docking study should help the identification of other protease inhibitors from fungus.

Inhibition of Amyloid β Aggregation by p-Terphenyl Derivatives Isolated from Boletopsis leucomelas

Inhibition of Amyloid β Aggregation by p-Terphenyl Derivatives Isolated from Boletopsis leucomelas

Antioxidant p-terphenyl compound, isolated from edible mushroom, Boletopsis leucomelas.

A new acetyl p-terphenyl derivative, boletopsin 15, was isolated from the ethyl acetate extract of fruit bodies of the Basidiomycete Boletopsis leucomelas, together with 4 known compounds. The structures of these compounds were elucidated by spectral analysis as well as by directly comparing the spectral data of the new compound with those of known compounds. The free radical-scavenging activity of the compounds was assayed using the 2,2-diphenyl-1-picrylhydrazyl scavenging method. The results showed that compounds 1 and 2 exhibited significant antioxidant activity (1: EC50=2.1 µm and 2: EC50=6.6 µm).

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.

Structure and Function of a Dual Reductase-Dehydratase Enzyme System Involved in p-Terphenyl Biosynthesis.

We report the identification of the ter gene cluster responsible for the formation of the p-terphenyl derivatives terfestatins B and C and echoside B from the Appalachian Streptomyces strain RM-5-8. We characterize the function of TerB/C, catalysts that work together as a dual enzyme system in the biosynthesis of natural terphenyls. TerB acts as a reductase and TerC as a dehydratase to enable the conversion of polyporic acid to a terphenyl triol intermediate. X-ray crystallography of the apo and substrate-bound forms for both enzymes provides additional mechanistic insights. Validation of the TerC structural model via mutagenesis highlights a critical role of arginine 143 and aspartate 173 in catalysis. Cumulatively, this work highlights a set of enzymes acting in harmony to control and direct reactive intermediates and advances fundamental understanding of the previously unresolved early steps in terphenyl biosynthesis.

Phase behaviour and crystal structures of 2',3'-difluorinated p-terphenyl derivatives.

The crystal structures of difluorine derivatives of p-terphenyls (nTm) have been determined by single-crystal X-ray diffraction. For the unsymmetrical substituted compounds 2',3'-difluoro-4-methyl-p-terphenyl (1T0, C19H14F2) and 4-ethyl-2',3'-difluoro-4''-methyl-p-terphenyl (1T2, C21H18F2), the crystal structure is disordered, with molecules statistically entering the crystal in up and down orientations, with full superposition of all the atoms, except for those of the terminal groups (H/methyl for 1T0 and methyl/ethyl for 1T2). For triclinic 2',3'-difluoro-4,4''-dimethyl-p-terphenyl (1T1, C20H16F2), with the space group P-1, the two crystallographically independent molecules have the same conformation, which is different from monoclinic 1T0 (space group C2) and 1T2 (space group C2/c). A common feature of the conformation of the three compounds is the noncoplanar twisted arrangement of the three rings of the p-terphenyl moiety. Two-dimensional (2D) Hirshfeld fingerprint plots are consistent with H...H and C...H contacts in the crystal packing. For the three compounds, the phase behaviour has been investigated by POM (Petra/Osiris/Molinspiration) and differential scanning calorimetry (DSC) analysis. 1T2 is mesogenic, with enantiotropic nematic behaviour.

Cytoprotective Activity of p-Terphenyl Polyketides and Flavuside B from Marine-Derived Fungi against Oxidative Stress in Neuro-2a Cells.

The influence of p-terphenyl polyketides 1–3 from Aspergillus candidus KMM 4676 and cerebroside flavuside B (4) from Penicillium islandicum (=Talaromyces islandicus) against the effect of neurotoxins, rotenone and paraquat, on Neuro-2a cell viability by MTT and LDH release assays and intracellular ROS level, as well as DPPH radical scavenging activity, was investigated. Pre-incubation with compounds significantly diminished the ROS level in rotenone- and paraquat-treated cells. It was shown that the investigated polyketides 1–3 significantly increased the viability of rotenone- and paraquat-treated cells in two of the used assays but they affected only the viability of paraquat-treated cells in the LDH release assay. Flavuside B statistically increased the viability of paraquat-treated cells in both MTT and LDH release assays, however, it increased the viability of rotenone-treated cells in the LDH release assay. Structure–activity relationships for p-terphenyl derivatives, as well as possible mechanisms of cytoprotective action of all studied compounds, were discussed.

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.

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.

Identification of HN252 as a potent inhibitor of protein phosphatase PPM1B.

Protein phosphatase 1B (PPM1B), a member of metal‐dependent protein serine/threonine phosphatase family, is involved in the regulation of several signalling pathways. However, our understanding of its substrate interaction and physiological functions is still largely limited. There is no reported PPM1B inhibitor to date. In this study, we identified HN252, a p‐terphenyl derivative, as a potent PPM1B inhibitor (Ki = 0.52 ± 0.06 µM). HN252 binding to PPM1B displayed remarkable and specific inhibition of PPM1B in both in vitro and ex vivo. With the aid of this small molecular inhibitor, we identified 30 proteins’ serine/threonine phosphorylation as potential substrates of PPM1B, 5 of which were demonstrated by immunoprecipitation, including one known (CDK2) and 4 novel ones (AKT1, HSP90B, β‐catenin and BRCA1). Furthermore, GO and KEGG analysis of dramatically phosphorylated proteins by PPM1B inhibition indicated that PPM1B plays roles in the regulation of multiple cellular processes and signalling pathways, such as gene transcription, inflammatory regulation, ageing and tumorigenesis. Our work provides novel insights into further investigation of molecular mechanisms of PPM1B.

Heterogeneous Pd/C-catalyzed, ligand free Suzuki–Miyaura coupling reaction furnishes new p-terphenyl derivatives

A series of new para-terphenyls derivatives have been efficiently synthesized by a ligand-free heterogeneous Pd/C-catalyzed two-fold Suzuki–Miyaura coupling reaction. Methyl 5-bromo-2-iodobenzoate was selected to react with a variety of different aryl boronic acids (2a-i). Nine new p-terphenyl derivatives (3a–i) were prepared and the structures were confirmed by several analytical techniques including infrared, spectroscopy, 1H and 13C NMR spectroscopy, mass spectrometry, and in the case of compound 3 b, by X-ray diffraction method. The new derivatives were obtained in very good yields (78–91%). This synthetic facile route is envisioned to improve the preparation of p-terphenyl-based natural products.