RESUMO
The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.
Assuntos
Antígeno B7-H1 , Simulação de Acoplamento Molecular , Receptor de Morte Celular Programada 1 , Ligação Proteica , Compostos de Terfenil , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Antígeno B7-H1/química , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/química , Humanos , Compostos de Terfenil/química , Compostos de Terfenil/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Sítios de LigaçãoRESUMO
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.
Assuntos
Basidiomycota , Compostos de Terfenil , Humanos , Basidiomycota/química , Compostos de Terfenil/química , Fenóis , Espectroscopia de Ressonância MagnéticaRESUMO
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.
Assuntos
Basidiomycota , Produtos Biológicos , Compostos de Terfenil , Anti-Inflamatórios , Basidiomycota/química , Simulação de Acoplamento Molecular , Inibidores de Proteases , Compostos de Terfenil/química , Proteases Específicas de UbiquitinaRESUMO
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.
Assuntos
Antineoplásicos , Compostos de Terfenil , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/farmacologia , Fungos , Humanos , Peptídeo Hidrolases , Compostos de Terfenil/química , Compostos de Terfenil/farmacologia , Proteases Específicas de UbiquitinaRESUMO
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.
Assuntos
Hidroliases/metabolismo , Oxirredutases/metabolismo , Compostos de Terfenil/química , Sequência de Aminoácidos , Arginina/química , Ácido Aspártico/química , Vias Biossintéticas , Catálise , Cristalografia por Raios X , Escherichia coli/metabolismo , Modelos Moleculares , Ligação Proteica , Streptomyces/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Aspergillus/efeitos dos fármacos , Endófitos/efeitos dos fármacos , Rhizophoraceae , Compostos de Terfenil/isolamento & purificação , Compostos de Terfenil/farmacologia , Aspergillus/fisiologia , Endófitos/fisiologia , Células HCT116 , Células HL-60 , Células HeLa , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/fisiologia , Células K562 , Células MCF-7 , Compostos de Terfenil/químicaRESUMO
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.
Assuntos
Aspergillus/química , Oceanos e Mares , Compostos de Terfenil/farmacologia , Antineoplásicos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Terfenil/química , Compostos de Terfenil/isolamento & purificaçãoRESUMO
In the course of searching for cytotoxic metabolites from insects associated actinomyces, two new natural p-terphenyl glycosides, strepantibin D (1) and strepantibin E (2), along with terferol (3), actinomycin D (4), actinomycin V (5) and actinomycin V0ß (6), were identified from the fermentation medium of a Streptomyces sp. which was obtained from the larva body of mud dauber wasp. Strepantibin D (1), previously reported as a synthetic derivative of terfestatin A, is firstly isolated as a natural p-terphenyl in this research. Strepantibin D (1) and terferol (3) showed medium cytotoxic activity against breast cancer cells MCF-7, MDA-MB-231 and BT-474. Actinomycins (4-6), especially actinomycin V (5), displayed remarkable cytotoxicity against breast cancer cells, with IC50 values ranging from 0.83 nM to 369.90 nM.
Assuntos
Dactinomicina/farmacologia , Streptomyces/química , Compostos de Terfenil/farmacologia , Vespas/microbiologia , Animais , Antineoplásicos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dactinomicina/química , Humanos , Larva/microbiologia , Compostos de Terfenil/químicaRESUMO
The defined structure of molecules bearing multiple stereogenic axes is of increasing relevance to materials science, pharmaceuticals, and catalysis. However, catalytic enantioselective approaches to control multiple stereogenic axes remain synthetically challenging. We report the catalytic synthesis of two-axis terphenyl atropisomers, with complementary strategies to both chlorinated and brominated variants, formed with high diastereo- and enantioselectivity. The chemistry proceeds through a sequence of two distinct dynamic kinetic resolutions: first, an atroposelective ring opening of Bringmann-type lactones produces a product with one established axis of chirality, and second, a stereoselective arene halogenation delivers the product with the second axis of chirality established. In order to achieve these results, a class of Brønsted basic guanidinylated peptides, which catalyze an efficient atroposelective chlorination, is reported for the first time. In addition, a complementary bromination is reported, which also establishes the second stereogenic axis. These bromo-terphenyls are accessible following the discovery that chiral anion phase transfer catalysis by C2-symmetric phosphoric acids allows catalyst control in the second stereochemistry-determining event. Accordingly, we established the fully catalyst-controlled stereodivergent synthesis of all possible chlorinated stereoisomers while also demonstrating diastereodivergence in the brominated variants, with significant levels of enantioselectivity in all cases.
Assuntos
Peptídeos/química , Compostos de Terfenil/síntese química , Catálise , Cinética , Estrutura Molecular , Estereoisomerismo , Compostos de Terfenil/químicaRESUMO
A small library of 120 compounds was established with seventy new alkylated derivatives of the natural product terphenyllin, together with 45 previous reported derivatives and four natural p-terphenyl analogs. The 70 new derivatives were semi-synthesized and evaluated for cytotoxic activities against four cancer cell lines. Interestingly, 2',4''-diethoxyterphenyllin, 2',4,4''-triisopropoxyterphenyllin, and 2',4''-bis(cyclopentyloxy)terphenyllin showed potent activities with IC50 values in a range from 0.13 to 5.51â µM, which were similar to those of the positive control, adriamycin. The preliminary structure-activity relationships indicated that the introduction of alkyl substituents including ethyl, allyl, propargyl, isopropyl, bromopropyl, isopentenyl, cyclopropylmethyl, and cyclopentylmethyl are important for improving the cytotoxicity.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Bibliotecas de Moléculas Pequenas/química , Compostos de Terfenil/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Aspergillus/química , Aspergillus/isolamento & purificação , Produtos Biológicos/síntese química , Produtos Biológicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Compostos de Terfenil/síntese química , Compostos de Terfenil/químicaRESUMO
A new p-terphenyl derivative aspergicandidusin A (1), a new cleistanthane diterpenoid 6-deoxyaspergiloid C (13), and 12 known compounds (2-12, and 14) were isolated from the mold Aspergillus candidus. The structures of the new compounds were elucidated by spectral analysis of NMR and MS data. The absolute configuration of C-1 in 13 was determined via the circular dichroism data of the [Rh2(OCOCF3)4] complex. Compounds 2-8 and 11 showed moderate inhibitory activity against K562 cell lines with the IC50 value in the range from 17.9 to 46.3 µM. Compound 13 exhibited moderate cytotoxicity against HepG2 cells with the IC50 value of 47.7 µM. Compounds 11 and 12 exhibited moderate activity against the growth of S. aureus with MIC value of 6.25 µM, respectively.
Assuntos
Aspergillus/metabolismo , Terpenos/metabolismo , Compostos de Terfenil/metabolismo , Triticum/microbiologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Aspergillus/classificação , Células Hep G2 , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Terpenos/química , Terpenos/farmacologia , Compostos de Terfenil/química , Compostos de Terfenil/farmacologiaRESUMO
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.
Assuntos
Actinobacteria/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Compostos de Terfenil/isolamento & purificação , Compostos de Terfenil/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Análise Espectral/métodos , Compostos de Terfenil/químicaRESUMO
BACKGROUND: In recent years, copper complexes have gradually become the focus of potential anticancer drugs due to their available redox properties and low toxicity. In this study, a novel mitochondrion-targeting copper (II) complex, [Cu (ttpy-tpp)Br2] Br (simplified as CTB), is first synthesized by our group. CTB with tri-phenyl-phosphine (TPP), a targeting and lipophilic group, can cross the cytoplasmic and mitochondrial membranes of tumor cells. The present study aims to investigate how CTB affects mitochondrial functions and exerts its anti-tumor activity in hepatoma cells. METHODS: Multiple molecular experiments including Flow cytometry, Western blot, Immunofluorescence, Tracker staining, Transmission Electron Microscopy and Molecular docking simulation were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo. RESULTS: CTB induced apoptosis via collapse of mitochondrial membrane potential (MMP), ROS production, Bax mitochondrial aggregation as well as cytochrome c release, indicating that CTB-induced apoptosis was associated with mitochondrial pathway in human hepatoma cells. Mechanistic study revealed that ROS-related mitochondrial translocation of p53 was involved in CTB-mediated apoptosis. Simultaneously, elevated mitochondrial Drp1 levels were also observed, and interruption of Drp1 activation played critical role in p53-dependent apoptosis. CTB also strongly suppressed the growth of liver cancer xenografts in vivo. CONCLUSION: In human hepatoma cells, CTB primarily induces mitochondrial dysfunction and promotes accumulation of ROS, leading to activation of Drp1. These stimulation signals accelerate mitochondrial accumulation of p53 and lead to the eventual apoptosis. Our research shows that CTB merits further evaluation as a chemotherapeutic agent for the treatment of Hepatocellular carcinoma (HCC).
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Dinaminas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organometálicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cobre/química , Cobre/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Compostos Organometálicos/química , Fosfinas/química , Fosfinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Compostos de Terfenil/química , Compostos de Terfenil/farmacologia , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismoRESUMO
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).
Assuntos
Antineoplásicos/química , Chaetomium/metabolismo , Compostos de Terfenil/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chaetomium/química , Dicroísmo Circular , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Compostos de Terfenil/farmacologiaRESUMO
Tumor cells are vulnerable to reactive oxygen species (ROS). However, it is still a challenge to induce ROS efficiently in tumor cells. In this study, cascade amplifiers of intracellular ROS based on charge-reversible mitochondria-targeted ZnO-TPP@D/H nanorods (NRs) were first developed for breast cancer therapy. The core-shell ZnO-TPP@D/H NR with a particle size of 179.60 ± 5.67 nm was composed of a core of a ZnO NR, an inner shell of triphenyl phosphonium (TPP), and an outer shell of heparin. Doxorubicin (DOX) was loaded on ZnO-TPP@D/H NRs with high drug loading efficiency of 22.00 ± 0.18%. The zeta potential of ZnO-TPP@D/H NRs varied from 24.00 ± 0.83 to -34.06 ± 0.87 mV after heparin coating, protecting ZnO-TPP@D/H NRs from nonspecific adsorption in circulation. Mitochondrial targeting was achieved after the degradation of heparin. Cellular uptake assays showed that ZnO-TPP@D/H NRs could accumulate in mitochondria. ROS generation assays showed that ZnO-TPP@D/H NRs could triple the intracellular ROS in 4T1 cells (highly metastatic breast cancer cells) than free DOX. Western blot demonstrated that ZnO-TPP@D/H NRs dramatically induced cell apoptosis in 4T1 cells. In vivo experiments suggested the antitumor potential of ZnO-TPP@D/H NRs.
Assuntos
Doxorrubicina/administração & dosagem , Heparina/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanotubos/química , Compostos Organofosforados/química , Espécies Reativas de Oxigênio/metabolismo , Compostos de Terfenil/química , Óxido de Zinco/química , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Doxorrubicina/química , Heparina/administração & dosagem , Neoplasias Mamárias Experimentais/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Compostos Organofosforados/administração & dosagem , Distribuição Aleatória , Compostos de Terfenil/administração & dosagem , Óxido de Zinco/administração & dosagemRESUMO
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.
Assuntos
Ascomicetos/metabolismo , Compostos de Terfenil/isolamento & purificação , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Compostos de Terfenil/química , Compostos de Terfenil/farmacologiaRESUMO
Four new highly oxygenated p-terphenyls, hawaiienols A-D (1-4), have been isolated from cultures of Paraconiothyrium hawaiiense, a fungus associated with the Septobasidium-infected insect Diaspidiotus sp.; their structures were elucidated primarily by NMR experiments. The absolute configurations of 1 and 2-4 were assigned by single-crystal X-ray diffraction analysis using Cu Kα radiation and via electronic circular dichroism calculations, respectively. Compound 1 incorporated the first naturally occurring 4,7-dioxatricyclo[3.2.1.03,6]octane unit in its p-terphenyl skeleton and showed cytotoxicity toward six human tumor cell lines.
Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Ascomicetos/metabolismo , Insetos/microbiologia , Compostos de Terfenil/química , Compostos de Terfenil/farmacologia , Animais , Ascomicetos/química , Linhagem Celular Tumoral , Dicroísmo Circular , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Difração de Raios XRESUMO
Three cyclopentanoids (phlebiopsin Aâ»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.
Assuntos
Aldeídos/isolamento & purificação , Antifúngicos/isolamento & purificação , Catecóis/isolamento & purificação , Ciclopentanos/isolamento & purificação , Doenças das Plantas/prevenção & controle , Polyporales/química , Compostos de Terfenil/isolamento & purificação , Agaricales/efeitos dos fármacos , Aldeídos/química , Aldeídos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Catecóis/química , Catecóis/farmacologia , Cromatografia Líquida , Ciclopentanos/química , Ciclopentanos/farmacologia , Fusarium/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Penicillium/efeitos dos fármacos , Doenças das Plantas/microbiologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/microbiologia , Polyporales/crescimento & desenvolvimento , Metabolismo Secundário , Compostos de Terfenil/química , Compostos de Terfenil/farmacologiaRESUMO
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), 2â³-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.
Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Aspergillus/química , Bactérias/efeitos dos fármacos , Poríferos/microbiologia , Animais , Anisomicina/análogos & derivados , Anisomicina/química , Anisomicina/isolamento & purificação , Anisomicina/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Farmacorresistência Bacteriana/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Pirrolidinas/química , Pirrolidinas/isolamento & purificação , Pirrolidinas/farmacologia , Compostos de Terfenil/química , Compostos de Terfenil/isolamento & purificaçãoRESUMO
An analytical method based on high resolution mass spectrometry coupled with liquid chromatography (LC-HRMS) for 25 quaternary phosphonium compounds (QPCs) and derived phosphine oxides (POs) was developed and validated. To investigate the occurrence and fate of QPCs in the aquatic environment, water, suspended solids and sediments from the rivers Rhine and Elbe (upper and middle Elbe as well as tidal Elbe) were analyzed, as well as samples from tributaries bearing significant loads of QPCs. For the first time, the quaternary phosphonium compound tetrabutylphosphonium (Bu4P+) was detected. In the river Elbe concentrations were determined of up to 4700 ng/L (surface water) and 1000⯵g/kg (sediment), respectively. Analysis of a time series of suspended solids (2005-2015) showed that QPCs have been present in the Elbe and Rhine catchment for at least one decade, with partly rising tendency. A degradation experiment with Rhine sediment revealed that triphenylphosphonium compounds (R-Ph3P+) and Bu4P+ are persistent in contact with sediment and suspended solids and tend to sorb onto sediment particles. Toxicological studies (reactive oxygen species (ROS) after substance exposure, Ames test, Micronucleus test, determination of cytotoxicity) with selected QPCs confirmed that all of them exhibit cytotoxicity and some even genotoxic potential at elevated concentrations, which emphasizes the need for an emission regulation of these compounds.