Characterization and optimization of a ß detector for 18F radio-guided surgery.

Radio-Guided Surgery (RGS) is a nuclear medicine technique to support the surgeon during surgery towards a complete tumor resection. It is based on intraoperative detection of radiation emitted by a radio-pharmaceutical that bounds selectively to tumoral cells. In the past years, an approach that exploits ß- emitting radiotracers has been pursued to overtake some limitations of the traditional RGS based on γ emission. A particle detector dedicated to this application, demonstrating very high efficiency to ß- particles and remarkable transparency to photons, has been thus developed. As a by-product, its characteristics suggested the possibility to utilize it with ß+ emitting sources, more commonly in use in nuclear medicine. In this paper, performances of such detector on 18F liquid sources are estimated by means of Monte Carlo simulations (MC) and laboratory measurements. The experimental setup with a 18F saline solution comprised a "positron signal" spot (a 7 × 10 mm cylinder representing the tumor residual), and a surrounding "far background" volume, that represented for the detector an almost isotropic source of annihilation photons. Experimental results show good agreement with MC predictions, thus confirming the expected performances of the detector with 18F, and the validity of the developed MC simulation as a tool to predict the gamma background determined by a diffuse source of annihilation photons.

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.

p-Terphenyl-based rigid stationary phases with embedded polar groups for liquid chromatography.

Terphenyls are important building blocks for a wide range of functional molecules. Among the three isomers, p-terphenyl (C18H14) is particularly useful for the construction of optical devices on account of its unique structure. Herein, two rigid stationary phases bearing p-terphenyl as an external moiety and variable embedded carbamate groups (p-TerC with one embedded carbamate group and p-TerC2 with two embedded carbamate group) were presented. The proposed stationary phases were characterized by various means and evaluated in reversed-phase (RP) mode, using different classes of analytes, including polycyclic aromatic hydrocarbons (PAHs), alkylbenzenes, 4-alkylbiphenyls, substituted ureas, sulfonylureas, substituted sulfanilamides and aromatic acids. The comparison with conventional C18, several other polar-embedded aromatic and C18 equivalents indicated p-terphenyl-based stationary phases were featured by multiple retention mechanisms, involving π-π interaction, charge-transfer interaction, hydrogen-bonding and hydrophobic interaction in RP mode. A unusually high specificity to the analytes with linear structures was observed, as exemplified by an irreversible adsorption of tetracene and a readily separation of tetraphene and chrysene. The aliphatic linker used in the proposed stationary phases was an influential factor for retentivity, selectivity and column efficiency. Interestingly, p-TerC2 was operable in normal-phase mode for the separation of certain PAHs through polar-related interactions. The linear, rigid polyphenyl structure of p-terphenyl endowed the new stationary phase with distinctive chromatographic properties, in contrast to those of the preceding counterparts bonded with alkyl and/or polynuclear aromatic moieties.

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.

Isolation and biosynthesis of daturamycins from Streptomyces sp. KIB-H1544.

Two novel diarylcyclopentenones daturamycin A and B (1 and 2), and one new p-terphenyl daturamycin C (3), along with three known congeners (4-6), were isolated from a rhizosphere soil-derived Streptomyces sp. KIB-H1544. The structures of new compounds were elucidated via a joint use of spectroscopic analyses and single-crystal X-ray diffractions. Compounds 1 and 2 belong to a rare class of tricyclic 6/5/6 diarylcyclopentenones, and compounds 3-6 possess a C-18 tricyclic aromatic skeleton. The biosynthetic gene cluster of daturamycins was identified through gene knockout and biochemical characterization experiments and the biosynthetic pathway of daturamycins was proposed.

Anti-inflammatory and anticancer p-terphenyl derivatives from fungi of the genus Thelephora.

Fungi from the genus Thelephora have been exploited to identify bioactive compounds. The main natural products characterized are para-terphenyl derivatives, chiefly represented by the lead anti-inflammatory compound vialinin A isolated from species T. vialis and T. terrestris. Different series of p-terphenyls have been identified, including vialinins, ganbajunins, terrestrins, telephantins and other products. Their mechanism of action is not always clearly identified, and different potential molecule targets have been proposed. The lead vialinin A functions as a protease inhibitor, efficiently targeting ubiquitin-specific peptidases USP4/5 and sentrin-specific protease SENP1 which are prominent anti-inflammatory and anticancer targets. Protease inhibition is coupled with a powerful inhibition of the cellular production of tumor necrosis factor TNFα. Other mechanisms contributing to the anti-inflammatory or anti-proliferative action of these p-terphenyl compounds have been invoked, including the formation of cytotoxic copper complexes for derivatives bearing a catechol central unit such vialinin A, terrestrin B and telephantin O. These p-terphenyl compounds could be further exploited to design novel anticancer agents, as evidenced with the parent compound terphenyllin (essentially found in Aspergillus species) which has revealed marked antitumor and anti-metastatic effects in xenograft models of gastric and pancreatic cancer. This review shed light on the structural and functional diversity of p-terphenyls compounds isolated from Thelephora species, their molecular targets and pharmacological properties.

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).

Structural diversity and biological activity of natural p-terphenyls.

p-Terphenyls are aromatic compounds consisting of a central benzene ring substituted with two phenyl groups, and they are mainly isolated from terrestrial and marine organisms. The central ring of p-Terphenyls is usually modified into more oxidized forms, e.g., para quinone and phenols. In some cases, additional ring systems were observed on the terphenyl-type core structure or between two benzene moieties. p-Terphenyls have been reported to have cytotoxic, antimicrobial, antioxidant and α-glucosidase inhibitory effects. In this review, we will mainly summarize the structural diversity and biological activity of naturally occurring p-Terphenyls referring to the research works published before. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-021-00117-8.

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.

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.

Antioxidant p-terphenyl compounds in the mushroom Boletopsis leucomelas (PERS.) FAYOD and how they change via cooking.

Antioxidant compounds in the mushroom Boletopsis leucomelas (PERS.) FAYOD were isolated using chromatographic methods, and their structures were determined via detailed analyses using high-resolution atmospheric pressure chemical ionization mass spectrometry and nuclear magnetic resonance. We identified five known p-terphenyl compounds (Bl-I, Bl-II, Bl-III, cycloleucomelon-leukopentaacetat, and Bl-IV) and one p-terphenyl new compound (Bl-VI); we determined the complete structure of cycloleucomelon-leukopentaacetat in this study. All these compounds possess potent lipid peroxidation-inhibiting activities. We further investigated changes in their chemical structures and antioxidant activities by applying heat (grilling, boiling, and microwave heating), and proved the production of two known p-terphenyl compounds (BI-V and boletopsin A) and one new p-terphenyl compound (BI-VII) via deacetylation of the original p-terphenyl compounds for the first time. We also found that DPPH radical scavenging activity was enhanced upon moderate heat cooking (boiling and microwave heating) due to changes in p-terphenyl compounds.

Remediation of contaminated sediments containing both organic and inorganic chemicals using ultrasound and ozone nanobubbles.

Most river sediments are contaminated with organic and inorganic pollutants and cause significant environmental damage and health risks. This research is evaluated an in-situ sediment remediation method using ultrasound and ozone nanobubbles to remove organic and inorganic chemicals in contaminated sediments. Contaminated sediment is prepared by mixing synthetic fine sediment with an organic (p-terphenyl) and an inorganic chemical (chromium). The prepared contaminated sediment is treated with ultrasound and ozone nanobubbles under different operating conditions. For the samples with the maximum initial concentration of 4211 mg/kg Cr and 1875 mg/kg p-terphenyl, average removal efficiencies are 71% and 60%, respectively, with 240 min of sonication with 2-min pulses, whereas 97.5% and 91.5% removal efficiencies are obtained for the same, respectively, as a single contaminant in the sediment. For the same maximum concentrations, the highest removal of p-terphenyl is 82.7% with 127.2 J/ml high energy density, and for Cr, it is 77.1% using the highest number of the treatment cycle and ozone usage with 78.75/ml energy density. The Cr highest removal efficiency of 87.2% is recorded with the reduced initial concentration of 1227 mg/kg with the highest treatment cycles. The Cr removal efficiency depends on the availability of oxidizing agents and the number of washing cycles of sediments, whereas P-terphenyl degradation is most likely influenced by the combined effects of oxidation and ultrasound-assisted pyrolysis and combustion of organics.

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.

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, ß-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.

Fabrication and Characterization of Anthracene Doped P-terphenyl Thin Films By Spin Coating Technique; Investigation of Fluorescence Properties.

Thin films of p-terphenyl luminophors doped by varying amounts of anthracene were prepared by using spin coating technique. The morphological, structural, and photophysical investigation of thin films of p-terphenyl as a function of anthracene concentration is studied by using scanning electron microscopy (SEM), X-ray diffraction (XRD), fluorescence spectroscopy and fluorescence microscopy. The results of XRD and SEM studies indicated that the doped p-terphenyl thin film is homogeneous as compared with a bare p-terphenyl thin film. The fluorescence spectroscopy results indicate complete quenching of p-terphenyl fluorescence and simultaneous sensitization of blue anthracene like emission towards the red side of the spectrum with maximum intensity at 410 nm. The blue intense emission of anthracene seen in fluorescence microscopy images is in agreement with observed fluorescence spectral results. A suitable mechanism of excitation energy transfer (EET) from p-terphenyl to anthracene molecules is proposed and discussed on the basis of energy level diagram. The efficient EET is believed to occur by the orientation of phenyl rings of p-terphenyl in excited state. As the concentration of doped anthracene increases, the fluorescence intensity of doped p-terphenyl and Full Width at Half Maximum (FWHM) found to be increased. The p-terphenyl film containing 0.65 moles of anthracene is of FWHM as low as 28.51 nm. Such narrow band blue emitting doped luminophors are of demand in light emitting diodes (OLED) and scintillation applications.

A new p-terphenyl derivative from the insect-derived fungus Aspergillus candidus Bdf-2 and the synergistic effects of terphenyllin.

A new p-terphenyl derivative 4″-deoxy-2'-methoxyterphenyllin (1), along with six known p-terphenyl derivatives (2-7), a known flavonoid derivative dechlorochlorflavonin (8) and a known fellutanine A (9), were isolated from the insect-derived strain of the fungus Aspergillus candidus Bdf-2, associated with Blaptica dubia. The structure of 1 was established by the analysis of the 1D and 2D NMR and HR-ESI-MS spectra. Compounds 1-9 were evaluated for antibacterial activities against Staphylococcus aureus ATCC29213, Escherichia coli ATCC25922 and Ralstonia solanacearum, and for antioxidant activities. Synergistic effects of compound 2 with the other compounds were also investigated. As a result, compound 6 displayed the best antibacterial activities in all single compound with MIC value of 32 µg/mL against S. aureus ATCC29213 and R. solanacearum, respectively. However, no antibacterial effect against E. coli ATCC25922 was detected from any single compound. The combination of 2 + 6 exhibited obvious synergistic effect against S. aureus ATCC29213 and the MIC value was 4 µg/mL. Compound 6 also showed the best antioxidant activity as a single compound with an IC50 value of 17.62 µg/mL. Combinations of 5 + 6, 2 + 4 + 5 and 2 + 4 + 5 + 6 displayed synergistic effect and their antioxidant activities were better than that of any single compound.

Voltammetry at Hexamethyl-P-Terphenyl Poly(Benzimidazolium) (HMT-PMBI)-Coated Glassy Carbon Electrodes: Charge Transport Properties and Detection of Uric and Ascorbic Acid.

We describe the voltammetric behavior of an anion-exchange membrane, hexamethyl-p-terphenyl poly(benzimidazolium) (HMT-PMBI). The anion-exchange properties of HMT-PMBI chemically modified electrodes were investigated using K4Fe(CN)6 and K2IrCl6 as redox probes. The permselectivity properties of HMT-PMBI chemically modified electrodes were ascertained using tris(2-2')bipyridyl-ruthenium(II) chloride Ru(bpy)32+. Cyclic voltammetry and chronoamperometry were utilized to extract parameters such as the concentration of the redox mediators inside the films and the apparent diffusion coefficients. We found the concentration of K4Fe(CN)6 and K2IrCl6 redox species within HMT-PMBI-coated films to be on the order of 0.04-0.1 mol·dm-3, and values of Dapp ca. 10-10-10-9 cm2·s-1. To evaluate the possibility of using such a polymer coating in electroanalysis, HMT-PMBI-modified electrodes were utilized for the voltammetric detection of uric acid in artificial urine, Surine® and ascorbic acid in Vitamin C samples. The results showed that HMT-PMBI-coated electrodes can detect uric acid in Surine® with a limit of detection (LoD) of 7.7 µM, sensitivity of 0.14 µA·µM-1·cm-2, and linear range between 5 µM and 200 µM, whereas for Vitamin C tablets, the LoD is 41.4 µM, the sensitivity is 0.08 µA·µM-1·cm-2, and the linear range is between 25 µM and 450 µM.

New p-terphenyl and benzoquinone metabolites from the bioluminescent mushroom Neonothopanus nambi.

Two new p-terphenyls, neonambiterphenyls A and B (1-2), a new benzoquinone, neonambiquinone A (3), together with six known sesquiterpenes (4-9), were isolated from the bioluminescent mushroom Neonothopanus nambi PW3. The isolated compounds were identified by mass, IR and spectroscopic analyses (1D and 2D NMR). Compounds 1-3 and 5-7 showed cytotoxicity against cancer cell lines such as KB, NCI-H187 and MCF-7 with IC50 values ranging from 1.45 to 49.31 µg/mL. In addition, compounds 1 and 5 showed cytotoxicity against Vero cells with IC50 values of 38.72 and 32.90 µg/mL, respectively.

Characterisation of a ß detector on positron emitters for medical applications.

PURPOSE: Radio Guided Surgery (RGS) is a technique that helps the surgeon to achieve an as complete as possible tumor resection, thanks to the intraoperative detection of particles emitted by a radio tracer that bounds to tumoral cells. In the last years, a novel approach to this technique has been proposed that, exploiting ß- emitting radio tracers, overtakes some limitations of established γ-RGS. In this context, a first prototype of an intraoperative ß particle detector, based on a high light yield and low density organic scintillator, has been developed and characterised on pure ß- emitters, like 90Y. The demonstrated very high efficiency to ß- particles, together with the remarkable transparency to photons, suggested the possibility to use this detector also with ß+ emitting sources, that have plenty of applications in nuclear medicine. In this paper, we present upgrades and optimisations performed to the detector to reveal such particles. METHODS: Laboratory measurement have been performed on liquid Ga68 source, and were used to validate and tune a Monte Carlo simulation. RESULTS: The upgraded detector has an ~80% efficiency to electrons above ~110keV, reaching a plateau value of ~95%. At the same time, the probe is substantially transparent to photons below ~200keV, reaching a plateau value of ~3%. CONCLUSIONS: The new prototype seems to have promising characteristics to perform RGS also with ß+ emitting isotopes.

Novel Metabolites from the Endophytic Fungus Chaetomium subaffine L01.

One natural p-terphenyl glycoside, gliocladinin C, and two furano-polyene derivatives, chaetominins A and B, were isolated from potato endophytic fungus Chaetomium subaffine. The absolute configurations of these compounds were elucidated by HR-ESI-MS, NMR, the DP4+ probabilities and electronic circular dichroism (ECD) spectra. Furthermore, gliocladinin C and chaetominin A showed cytotoxic activity against two selected human tumor cell lines (Hep-2 and HepG-2).