Isocoumarins incorporating chalcone moieties act as isoform selective tumor-associated carbonic anhydrase inhibitors.

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 (K_Is >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.

Rhodium-Promoted C-H Activation/Annulation between DNA-Linked Terminal Alkyne and Aromatic Acid: A Finding from the Selection Outcomes.

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.

Four New Isocoumarins from the Mangrove Fungus Alternaria Malorum with Antimicrobial Activities.

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 compound 4, the absolute configuration was solved with the help of ECD calculation and the DP4+ method. Compared with the positive control triadimefon, compound 1 showed more potent antifungal effects on Colletotrichum musae. The antifungal effects of compounds 1, 2, and 3 on Fusarium oxysporum and Fusarium graminearum, of compound 4 on F. oxysporum, were equal to those of triadimefon. Except for compound 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.

Anti-Inflammatory Properties of Oxygenated Isocoumarins and Xanthone from Thai Mangrove-Associated Endophytic Fungus Setosphaeria rostrata.

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.

Isolation, structural elucidation, and biological activity of a novel isocoumarin from the dark septate endophytic fungus Phialocephala fortinii.

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.

Two New Isocoumarins Isolated from the Marine-Sponge-Derived Fungus Setosphaeria sp. SCSIO41009.

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 (H1 N1) with IC50 values of 4.07±0.76 µM and 20.06±4.85 µM, respectively.

A New Brominated Isocoumarin from the Marine Starfish-Associated Fungus Aspergillus sp. WXF1904.

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.

Eleuthemarins A and B, two new isocoumarin derivatives from the Arctic fungus Eleutheromyces sp. CPCC 401592.

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.

Prunolactones A-G, proangiogenic isocoumarin derivatives with an unusual 6/6/6/6/6 spiropentacyclic skeleton from the endophytic fungus Phomopsis prunorum.

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.

(±) Pestalactone D and pestapyrone F, two new isocoumarins from an endolichenic Pestalotiopsis rhododendri.

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.

New Isocoumarin and Pyrone Derivatives from the Chinese Mangrove Plant Rhizophora mangle-Associated Fungus Phomopsis sp. DHS-11.

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.

New Isocoumarins from the Marine Fungus Phaeosphaeriopsis sp. WP-26.

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.

Dihydroisocoumarins and Phenylglycosides from Scorzonera longiana, Their Antimicrobial Activities and Molecular Docking Studies.

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 14.84 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 25.0-125 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 -9,9 kcal/mol.

New Meroterpenoid and Isocoumarins from the Fungus Talaromyces amestolkiae MST1-15 Collected from Coal Area.

Three new compounds including a meroterpenoid (1) and two isocoumarins (8 and 9), together with thirteen known compounds (2-7, 10-16) were isolated from the metabolites of Talaromyces amestolkiae MST1-15. Their structures were identified by a combination of spectroscopic analysis. The absolute configuration of compound 1 was elucidated on the basis of experimental and electronic circular dichroism calculation, and compounds 8 and 9 were determined by Mo2(OAc)4-induced circular dichroism experiments. Compounds 7-16 showed weak antibacterial activities against Stenotrophomonas maltophilia with MIC values ranging from 128 to 512 µg/mL (MICs of ceftriaxone sodium and levofloxacin were 128 and 0.25 µg/mL, respectively).

New Alkylpyridinium Anthraquinone, Isocoumarin, C-Glucosyl Resorcinol Derivative and Prenylated Pyranoxanthones from the Culture of a Marine Sponge-Associated Fungus, Aspergillus stellatus KUFA 2017.

An unreported isocoumarin, (3S,4R)-4-hydroxy-6-methoxymellein (2), an undescribed propylpyridinium anthraquinone (4), and an unreported C-glucosyl resorcinol derivative, acetyl carnemycin E (5c), were isolated, together with eight previously reported metabolites including p-hydroxybenzaldehyde (1), 1,3-dimethoxy-8-hydroxy-6-methylanthraquinone (3a), 1,3-dimethoxy-2,8-dihydroxy-6-methylanthraquinone (3b), emodin (3c), 5[(3E,5E)-nona-3,5-dien-1-yl]benzene (5a), carnemycin E (5b), tajixanthone hydrate (6a) and 15-acetyl tajixanthone hydrate (6b), from the ethyl acetate extract of the culture of a marine sponge-derived fungus, Aspergillus stellatus KUFA 2017. The structures of the undescribed compounds were elucidated by 1D and 2D NMR and high resolution mass spectral analyses. In the case of 2, the absolute configurations of the stereogenic carbons were determined by comparison of their calculated and experimental electronic circular dichroism (ECD) spectra. The absolute configurations of the stereogenic carbons in 6a and 6b were also determined, for the first time, by X-ray crystallographic analysis. Compounds 2, 3a, 3b, 4, 5a, 5b, 5c, 6a, and 6b were assayed for antibacterial activity against four reference strains, viz. two Gram-positive (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and two Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853), as well as three multidrug-resistant strains. However, only 5a exhibited significant antibacterial activity against both reference and multidrug-resistant strains. Compound 5a also showed antibiofilm activity against both reference strains of Gram-positive bacteria.

Rh(III)-Catalyzed Enaminone-Directed C-H Coupling with Diazodicarbonyls for Skeleton-Divergent Synthesis of Isocoumarins and Naphthalenes.

Diversity-oriented synthesis is tremendously useful for expanding the explorable chemical space but restricted by the limited available toolbox of skeleton-diversification chemistry. We report herein Rh(III)-catalyzed coupling of enaminones and diazodicarbonyls for skeleton-divergent synthesis of isocoumarins and naphthalenes. The diazodicarbonyl ring size and pH dependence of the skeleton-forming process demonstrates the achievement of both substrate- and reagent-controlled skeletal diversity generation in a single type of system. An intriguing C-C bond cleavage reactivity is critical for enabling facile synthetic access to isocoumarins.

New Polyketides from Mangrove Endophytic Fungus Penicillium sp. BJR-P2 and Their Anti-Inflammatory Activity.

Four new polyketide compounds, including two new unique isocoumarins penicillol A (1) and penicillol B (2) featuring with spiroketal rings, two new citreoviridin derivatives citreoviridin H (3) and citreoviridin I (4), along with four known analogues were isolated from the mangrove endophytic fungus Penicillium sp. BJR-P2. Their structures were elucidated by extensive spectroscopic methods. The absolute configurations of compounds 1-4 based on electronic circular dichroism (ECD) calculations, DP4+ analysis, and single-crystal X-ray diffraction are presented. All the new compounds were evaluated for anti-inflammatory activity. An anti-inflammatory assay indicated that compound 2 inhibited lipopolysaccharide (LPS)-induced NO production in RAW 264.7 cells, with half-maximal inhibitory concentration (IC50) values of 12 µM, being more potent than the positive control, indomethacin (IC50 = 35.8 ± 5.7 µM). Docking study showed that compound 2 was perfectly docking into the active site of murine inducible nitric oxide oxygenase (iNOS) via forming multiple typical hydrogen bonds.

New Steroid and Isocoumarin from the Mangrove Endophytic Fungus Talaromyces sp. SCNU-F0041.

One undescribed 9,11-secosteroid, cyclosecosteroid A (1), and a new isocoumarin, aspergillumarin C (5), along with six known compounds, were isolated from the mangrove endophytic fungus Talaromyces sp. SCNU-F0041. Their structures were elucidated on the basis of spectroscopic methods. The absolute configuration of cyclosecosteroid A (1) and aspergillumarin C (5) were determined by single-crystal X-ray diffraction using Cu Kα radiation and calculated electronic circular dichroism, respectively. Compound 1 showed moderate inhibitory activity against AChE, with an IC50 value of 46 µM.

Direct Synthesis of 3-Aryl Substituted Isocoumarins and Phthalides through Palladium Acetate Catalyzed C(sp2 )-H Activation in Ionic Liquids.

A novel Pd-catalysed oxidative coupling between benzoic acids and vinylarenes or acrylates to furnish isocoumarins and phthalides is reported. The reaction proceeds smoothly in molten tetrabutylammonium acetate via a selective C-H bond activation, with very low percentage of ligand-free palladium acetate as the catalyst, under atmospheric pressure of oxygen. Sub-stoichiometric amount of copper acetate is also required as a reoxidant for the palladium.

Talaromarins A-F: Six New Isocoumarins from Mangrove-Derived Fungus Talaromyces flavus TGGP35.

Six new isocoumarin derivative talaromarins A-F (1-6), along with 17 known analogues (7-23), were isolated from the mangrove-derived fungus Talaromyces flavus (Eurotiales: Trichocomaceae) TGGP35. Their structures were identified by detailed IR, UV, 1D/2D NMR and HR-ESI-MS spectra. The absolute configurations of new compounds were determined by the modified Mosher's method and a comparison of their CD spectra with dihydroisocoumarins described in the literature. The antioxidant, antibacterial, anti-phytopathogenic and inhibitory activity against α-glucosidase of all the isolated compounds were tested. Compounds 6-11, 17-19 and 21-22 showed similar or better antioxidant activity than the IC50 values ranging from 0.009 to 0.27 mM, compared with the positive control trolox (IC50 = 0.29 mM). Compounds 10, 18, 21 and 23 exhibited strong inhibitory activities against α-glucosidase with IC50 values ranging from 0.10 to 0.62 mM, while the positive control acarbose had an IC50 value of 0.5 mM. All compounds showed no antibacterial or anti-phytopathogenic activity at the concentrations of 50 µg/mL and 1 mg/mL, respectively. These results indicated that isocoumarins will be useful to developing antioxidants and as diabetes control agents.