RESUMO
Two new C23-steroids derivatives, cyclocitrinoic acid A (1) and cyclocitrinoic acid B (2), and a new isocoumarin metabolite, (3R,4S)-6,8-dihydroxy-3,4,5-trimethyl-7-carboxamidelisocoumarin (10), together with 12 known compounds (3-9, 11-15) were isolated from the mangrove-sediment fungus Penicillium sp. SCSIO 41429. The structures of the new compounds were comprehensively characterized by 1D and 2D NMR, HRESIMS and ECD calculation. All isolates were evaluated for pancreatic lipase (PL) inhibitory and antioxidant activities. The biological evaluation results revealed that compounds 2, 14 and 15 displayed weak or moderate inhibition against PL, with IC50 values of 32.77, 5.15 and 2.42 µM, respectively. In addition, compounds 7, 12 and 13 showed radical scavenging activities against DPPH, with IC50 values of 64.70, 48.13, and 75.54 µM, respectively. In addition, molecular docking results indicated that these compounds had potential for PL inhibitory and antioxidant activities, which provided screening candidates for antioxidants and a reduction in obesity.
Assuntos
Antioxidantes , Sedimentos Geológicos , Isocumarinas , Lipase , Simulação de Acoplamento Molecular , Penicillium , Penicillium/metabolismo , Penicillium/química , Isocumarinas/farmacologia , Isocumarinas/química , Isocumarinas/isolamento & purificação , Lipase/antagonistas & inibidores , Lipase/metabolismo , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Sedimentos Geológicos/microbiologia , Concentração Inibidora 50 , Rhizophoraceae/microbiologia , Estrutura MolecularRESUMO
Aim: A series of isocoumarin-chalcone hybrids were prepared and assays for the inhibition of four isoforms of human carbonic anhydrase (hCA; EC 4.2.1.1), hCA I, II, IX and XII. Materials & methods: Isocoumarin-chalcone hybrids were synthesized by condensing acetyl-isocoumarin with aromatic aldehydes. They did not significantly inhibit off-target cytosolic isoforms hCA I and II (KI >100 µM) but acted as low micromolar or submicromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Results & conclusion: Our work provides insights into a new and scarcely investigated chemotype which provides interesting tumor-associated CA inhibitors, considering that some such derivatives like sulfonamide SLC-0111 are in advanced clinical trials for the management of metastatic advanced solid tumors.
A series of isocoumarinchalcone hybrids was prepared and assays for the inhibition of four isoforms of the metalloenzyme carbonic anhydrase (CA; EC 4.2.1.1), i.e., human (h) isoforms hCA I, II, IX and XII. Isocoumarins were less investigated as inhibitors of this enzyme. Here we show that the isocoumarinchalcone hybrids do not significantly inhibit the off-target cytosolic isoforms hCA I and II (KIs >100 µM) but act as low micromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Our work thus provides insights into a new and scarcely investigated chemotype which may provide interesting tumor-associated CA inhibitors, because some such compounds, e.g., the sulfonamide SLC-0111, are presently in advanced clinical trials for the management of metastatic advanced solid tumors.
Assuntos
Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Isocumarinas , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Humanos , Anidrases Carbônicas/metabolismo , Isocumarinas/química , Isocumarinas/farmacologia , Isocumarinas/síntese química , Chalcona/química , Chalcona/farmacologia , Relação Estrutura-Atividade , Isoenzimas/metabolismo , Isoenzimas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Estrutura Molecular , Chalconas/química , Chalconas/farmacologia , Chalconas/síntese químicaRESUMO
Inspired by previous selection outcomes, we investigated and developed a rhodium-promoted C-H activation/annulation reaction of DNA-linked terminal alkynes and aromatic acids. This reaction exhibits excellent efficiency with high conversions and a broad substrate scope. Most importantly, the unique DEL-compatible conditions provide a better scenario for yielding an isocoumarin scaffold compared to conventional organic reaction conditions, and this newly developed on-DNA method has confirmed its feasibility in preparing DNA-encoded libraries.
Assuntos
Alcinos , DNA , Ródio , Ródio/química , Alcinos/química , Estrutura Molecular , DNA/química , Catálise , Isocumarinas/química , Isocumarinas/síntese químicaRESUMO
4-Chloroisocoumarin compounds have broad inhibitory properties against serine proteases. Here, we show that selected 3-alkoxy-4-chloroisocoumarins preferentially inhibit the activity of the conserved serine protease High-temperature requirement A of Chlamydia trachomatis. The synthesis of a new series of isocoumarin-based scaffolds has been developed, and their anti-chlamydial properties were investigated. The structure of the alkoxy substituent was found to influence the potency of the compounds against High-temperature requirement A, and modifications to the C-7 position of the 3-alkoxy-4-chloroisocoumarin structure attenuate anti-chlamydial properties.
Assuntos
Álcoois , Chlamydia trachomatis , Inibidores de Proteases , Inibidores de Proteases/farmacologia , Terapia Enzimática , Isocumarinas , Serina Endopeptidases , Serina ProteasesRESUMO
Four new isocoumarins, alternariethers A-C (1-3) and alternariester (4) were separated from the fermentation of the fungus Alternaria malorum FL39, purified from Myoporum bontioides. Their structures were ascertained using NMR and HR-ESI-MS spectroscopy. For compoundâ 4, the absolute configuration was solved with the help of ECD calculation and the DP4+ method. Compared with the positive control triadimefon, compoundâ 1 showed more potent antifungal effects on Colletotrichum musae. The antifungal effects of compoundsâ 1, 2, and 3 on Fusarium oxysporum and Fusarium graminearum, of compoundâ 4 on F. oxysporum, were equal to those of triadimefon. Except for compoundâ 4 which was inactive against Escherichia coli with O78 serotype, all compounds showed moderate or weak antibacterial activity against Staphylococcus aureus ATCC 6538 and E. coli with O6 or O78 serotype.
Assuntos
Alternaria , Antibacterianos , Escherichia coli , Fusarium , Isocumarinas , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Alternaria/química , Alternaria/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Isocumarinas/química , Isocumarinas/farmacologia , Isocumarinas/isolamento & purificação , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Fusarium/efeitos dos fármacos , Colletotrichum/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Myoporum/química , Myoporum/metabolismoRESUMO
A novel isocoumarin was isolated from the mycelia of the dark septate endophytic fungus Phialocephala fortinii. The chemical structure was determined to be 8-hydroxy-6-methoxy-3,7-dimethyl-1H-2-benzopyran-1-one based on mass spectrometry, 1H-nuclear magnetic resonance (NMR), and 13C-NMR spectroscopic analyses, including 2D-NMR experiments. The isolated compound inhibited root growth of Arabidopsis thaliana, suggesting its potential as a plant growth regulator.
Assuntos
Arabidopsis , Ascomicetos , Isocumarinas , Raízes de Plantas , Isocumarinas/química , Isocumarinas/farmacologia , Isocumarinas/isolamento & purificação , Ascomicetos/química , Raízes de Plantas/microbiologia , Arabidopsis/microbiologia , Espectroscopia de Ressonância Magnética , Endófitos/química , Micélio/crescimento & desenvolvimento , Micélio/química , Micélio/efeitos dos fármacos , Reguladores de Crescimento de Plantas/farmacologia , Reguladores de Crescimento de Plantas/química , Estrutura MolecularRESUMO
Chronic inflammation plays a crucial role in the development and progression of numerous chronic diseases. To search for anti-inflammatory metabolites from endophytic fungi isolated from plants growing in Thai mangrove areas, a chemical investigation of those fungi was performed. Five new oxygenated isocoumarins, setosphamarins A-E (1-5) were isolated from the EtOAc extract of an endophytic fungus Setosphaeria rostrata, along with four known isocoumarins and one xanthone. Their structures were determined by extensive spectroscopic analysis. The absolute configurations of the undescribed compounds were established by comparative analysis between experimental and calculated circular dichroism (ECD) spectroscopy. All the compounds were evaluated for their anti-inflammatory activity by monitoring nitric oxide inhibition in lipopolysaccharide-induced macrophage J774A.1 cells. Only a xanthone, ravenelin (9), showed potent activity, with an IC50 value of 6.27 µM, and detailed mechanistic study showed that it suppressed iNOS and COX-2 expression.
Assuntos
Ascomicetos , Xantonas , Isocumarinas/química , Tailândia , Ascomicetos/química , Anti-Inflamatórios/farmacologia , Xantonas/farmacologia , Estrutura MolecularRESUMO
Two new dihydroisocoumarins, exserolides L and M (1 and 2), along with six known compounds (3-8) were isolated from the extract of the marine-sponge-derived fungus Setosphaeria sp. SCSIO41009. Their structures were established by spectroscopic analyses. The absolute configurations of two new compounds were determined by modified Mosher's method and ECD data. Compounds 1 and 4 showed significant antiviral activities against A/Puerto Rico/8/34 H274Y (H1â N1) with IC50 values of 4.07±0.76â µM and 20.06±4.85â µM, respectively.
Assuntos
Ascomicetos , Isocumarinas , Estrutura Molecular , Isocumarinas/química , Ascomicetos/químicaRESUMO
Based on the one strain many compounds strategy, a new brominated isocoumarin, 5-bromo-6,8-dihydroxy-3,7-dimethylisocoumarin (1), along with four new natural products, methyl 3-bromo-2,4-dihydroxy-6-methylbenzoate (2), methyl 2-bromo-4,6-dihydroxybenzoate (3), (E)-3-(3-bromo-4-hydroxyphenyl) acrylic acid (4) and 4-hydroxy-3-methyl-6-phenyl-2H-pyran-2-one (5), and four known compounds, methyl orsellinate (6), 4-hydroxy-3-methyl-6-(1-methyl-1-propenyl)-2H-pyran-2-one (7), pilobolusate (8) and cis-ferulic acid (9), were isolated from the ethyl acetate extract of the fungus Aspergillus sp. WXF1904 under the condition of adding bromine salt to the production medium. The structures of the new compounds were established by analysis of NMR and MS data. Compounds (1-9) were evaluated for inhibitory activity of acetylcholinesterase and pancreatic lipase, the new compound 1, known compounds 6 and 7 displayed weak inhibitory activity against acetylcholinesterase, compounds 2, 5, 7 and 8 showed weak inhibitory activity against pancreatic lipase.
Assuntos
Acetilcolinesterase , Isocumarinas , Aspergillus/química , Fungos , Isocumarinas/química , Lipase , Estrutura Molecular , Benzoatos/químicaRESUMO
Seven novel isocoumarins, prunolactones A-G (1-7), featuring an unusual 6/6/6/6/6 spiropentacyclic skeleton, together with two biosynthetic precursors phomopsilactone (8) and methyl 3-epi-shikimate (9), were isolated from the endophytic fungus Phomopsis prunorum guided by UPLC-QTOF-MS and 1H NMR spectroscopic analytical techniques. Their structures including absolute configurations of 1-7 were elucidated based on extensive spectroscopic data, X-ray diffraction analysis, and ECD calculations. Biogenetically, compounds 1-7 are proposed to be derived from polyketide and shikimate pathways via key intermolecular Diels - Alder reactions. Compounds 2, 3, and 7 showed significant in vivo proangiogenic activity in transgenic zebrafish.
Assuntos
Isocumarinas , Peixe-Zebra , Animais , Fungos/metabolismo , Isocumarinas/farmacologia , Isocumarinas/química , Estrutura Molecular , Esqueleto/metabolismo , Peixe-Zebra/metabolismoRESUMO
Two new isocoumarin derivatives, eleuthemarins A (1) and B (2), were isolated from the Arctic fungus Eleutheromyces sp. CPCC 401592. Their structures and absolute configurations were elucidated through spectroscopic methods, quantum chemical calculations of NMR shifts, and calculated electronic circular dichroism. This is the first report for the chemical investigation of the genus Eleutheromyces. Compounds 1 and 2 showed selective cytotoxic activities against H460, A549, and HCT116 cancer cell lines with IC50 values in the range of 24.1-57.3 µM, respectively. Compound 1 displayed weak antibacterial activities.
Assuntos
Ascomicetos , Isocumarinas , Humanos , Isocumarinas/farmacologia , Isocumarinas/química , Antibacterianos/química , Espectroscopia de Ressonância Magnética , Células HCT116 , Estrutura MolecularRESUMO
Coumarins, isocoumarins and their derivatives are polyketides abundant in fungal metabolites. Although they were first discovered over 50 years ago, the biosynthetic process is still not entirely understood. Herein, we report the activation of a silent nonreducing polyketide synthase that encodes a C7-methylated isocoumarin, similanpyrone B (1), in a marine-derived fungus Simplicillium lamellicola HDN13-430 by heterologous expression. Feeding studies revealed the host enzymes can change 1 into its hydroxylated derivatives pestapyrone A (2). Compounds 1 and 2 showed moderate radical scavenging activities with ED50 values of 67.4 µM and 104.2 µM. Our discovery fills the gap in the enzymatic elucidation of naturally occurring C7-methylated isocoumarin derivatives.
Assuntos
Hypocreales , Isocumarinas , Policetídeo Sintases , Cumarínicos/farmacologiaRESUMO
Three isocoumarins, including two new compounds, (±) pestalactone D (1) and pestapyrone F (2), as well as one known compound, pestapyrone D (3), were isolated from the culture of the endolichenic Pestalotiopsis rhododendri LF-19-12. The planar structures of all compounds were elucidated by NMR and MS spectra. And the absolute configurations of 1 were confirmed by single crystal X-ray diffraction analysis, indicative of it as a racemate of 4S/12S and 4R/12R enantiomers. Compound 1 exhibited weak anti-coronaviral activity against human coronavirus HCoV-229E with an EC50 of 77.61 µM. Based on the bioinformatics analysis, the biosynthetic pathway of 1 has been proposed.
Assuntos
Isocumarinas , Humanos , Isocumarinas/farmacologia , Isocumarinas/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Fungi in the genus Talaromyces occur in every environment in both terrestrial and marine contexts, where they have been quite frequently found in association with plants and animals. The relationships of symbiotic fungi with their hosts are often mediated by bioactive secondary metabolites, and Talaromyces species represent a prolific source of these compounds. This review highlights the biosynthetic potential of marine-derived Talaromyces strains, using accounts from the literature published since 2016. Over 500 secondary metabolites were extracted from axenic cultures of these isolates and about 45% of them were identified as new products, representing a various assortment of chemical classes such as alkaloids, meroterpenoids, isocoumarins, anthraquinones, xanthones, phenalenones, benzofurans, azaphilones, and other polyketides. This impressive chemodiversity and the broad range of biological properties that have been disclosed in preliminary assays qualify these fungi as a valuable source of products to be exploited for manifold biotechnological applications.
Assuntos
Produtos Biológicos , Policetídeos , Talaromyces , Animais , Produtos Biológicos/química , Policetídeos/química , Biotecnologia , IsocumarinasRESUMO
Mangrove-associated fungi are important sources for the discovery of new bioactive natural products. Three new isocoumarins (1-3) and one new pyrone derivative (4) were isolated from the ethyl acetate extract of the fermentation broth of the mangrove endophytic fungus Phomopsis sp. DHS-11. Nuclear magnetic resonance (NMR) spectroscopy (one-dimensional and two-dimensional) and mass spectrometry were used to determine the structures of these new compounds. The absolute configurations for the new isocoumarins 1-3 were determined by comparing their experimental and calculated electronic circular dichroism (ECD) spectra, while the configuration for the new pyrone-derivative 4 was tentatively solved by comparison of its 13C NMR data with reported data. In the biological activity test, compounds 1 and 3 showed cytotoxic activity against HeLa cells with IC50 values of 11.49 ± 1.64 µM and 8.70 ± 0.94 µM, respectively. The initial structure and activity relationship (SAR) analysis revealed that the length of the side chain at C-3 for isocoumarin-type compounds 1-3 could affect the cytotoxicity against HeLa cells. Compound 4 exhibited cytotoxic activities against human hepatoma cells HepG2 with an IC50 value of 34.10 ± 2.92 µM. All compounds have no immunosuppressive activity.
Assuntos
Antineoplásicos , Rhizophoraceae , Humanos , Antineoplásicos/farmacologia , Fungos , Células HeLa , Isocumarinas/química , Estrutura Molecular , Phomopsis , Pironas/farmacologia , Rhizophoraceae/microbiologiaRESUMO
Cladosporin, a unique natural product from the fungus Cladosporium cladosporioides, exhibits nanomolar inhibitory activity against Plasmodium falciparum by targeting its cytosolic lysyl-tRNA synthetase (PfKRS) to inhibit protein biosynthesis. Due to its exquisite selectivity towards pathogenic parasites, cladosporin has become a very promising lead compound for developing antiparasitic drugs to treat drug-resistant malaria and cryptosporidiosis infections. Here we review the recent research progress of cladosporin covering aspects of the chemical synthesis, biosynthesis, bioactivity, cellular target and structure-activity relationship.
Assuntos
Antimaláricos , Lisina-tRNA Ligase , Malária Falciparum , Malária , Humanos , Isocumarinas/metabolismo , Plasmodium falciparum/metabolismo , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antimaláricos/metabolismo , Malária Falciparum/tratamento farmacológicoRESUMO
Five new isocoumarins, phaeosphaerins A-E (1-5), were isolated from the fermentation broth of the marine fungus Phaeosphaeriopsis sp. WP-26, along with one known isocoumarin, 6,8-dihydroxy-7-methoxy-3-methylisocoumarin (6), and two known pimarane-type diterpenes, diaportheins A (7) and B (8). Their structures were elucidated via NMR experiments, X-ray diffraction analysis, and comparison of the experimental and computed ECD curves. Compounds 1-7 displayed weak neuroprotective effects against H2O2-induced damage in SH-SY5Y cells. Moreover, compound 8 showed cytotoxicity against BEL-7402, SGC-7901, K562, A549, and HL-60 cell lines.
Assuntos
Ascomicetos , Neuroblastoma , Humanos , Isocumarinas/química , Peróxido de Hidrogênio , Ascomicetos/química , Espectroscopia de Ressonância Magnética , Abietanos , Estrutura MolecularRESUMO
Five new phenyl dihydroisocoumarin glycosides (1-5) and two known compounds (6-7) were identified from the butanol fraction of Scorzonera longiana. The structures of 1-7 were elucidated based on spectroscopic methods. Antimicrobial, antitubercular, and antifungal evaluation of compounds 1-7 were carried out using the microdilution method against nine microorganisms. Compound 1 was active only against Mycobacterium smegmatis (Ms) with a MIC value of 14.84â µg/mL. All tested compounds (1-7) were active against Ms but only compounds 3-7 were active against fungi (C. albicans, S. cerevisiae) with MIC values of 25.0-125â µg/mL. In addition, molecular docking studies were conducted against Ms DprE1 (PDB ID: 4F4Q), Mycobacterium tuberculosis (Mbt) DprE1 (PDB ID: 6HEZ), and arabinosyltransferase C (EmbC, PDB ID: 7BVE) enzymes. Compounds 2, 5, and 7 are the most effective Ms 4F4Q inhibitors. Compound 4 was the most promising inhibitory activity on Mbt DprE with the lowest binding energy of -9,9â kcal/mol.
Assuntos
Anti-Infecciosos , Glicosídeos , Isocumarinas , Mycobacterium tuberculosis , Scorzonera , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Antituberculosos/farmacologia , Antituberculosos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Saccharomyces cerevisiae , Scorzonera/química , Isocumarinas/química , Isocumarinas/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologiaRESUMO
A series of new noscapinoids designed; synthesized and assessed whether its 3-ylidenephthalide and isocoumarin conjugates improved cytotoxicity. Cu-catalysed Sonogashira coupling of N-propargyl noscapine with 2-bromobenzoic acids followed by in-situ substrate-directed 5-exo-dig or 6-endo-dig cyclization produced 3-ylidenephthalide 6 a-6 f and isocoumarin 7 a-7 h analogues in very good yields. In comparison to the lead drug, noscapine, all the newly synthesised derivatives exhibited strong cytotoxic potential inâ vitro with IC50 ranging from 5.4â µM to 39.5â µM across the evaluated panel of cancer cell lines, without harming normal cells (IC50 >300â µM).
Assuntos
Antineoplásicos , Neoplasias , Noscapina , Humanos , Isocumarinas/farmacologia , Isocumarinas/uso terapêutico , Noscapina/uso terapêutico , Neoplasias/tratamento farmacológico , CiclizaçãoRESUMO
A practical method to access amino-isocoumarins catalyzed by a Rh(III) complex through redox-neutral C-H/O-H annulation has been disclosed. The use of N-functionalized cyclic carbonates is crucial to facilitate the catalytic turnover, and a broad spectrum of amino-isocoumarin derivatives were prepared with satisfactory yields. Amino-isocoumarin estrone conjugated with a selenocyano functionality was identified to be nearly four times as active as the marketed drug abiraterone against T47D cancer cells.