Chaetoxylariones A-G: undescribed chromone-derived polyketides from co-culture of Chaetomium virescens and Xylaria grammica enabled via the molecular networking strategy.

By co-culturing two endophytic fungi (Chaetomium virescens and Xylaria grammica) collected from the medicinal and edible plant Smilax glabra Roxb. and analyzing them with MolNetEnhancer module on GNPS platform, seven undescribed chromone-derived polyketides (chaetoxylariones A-G), including three pairs of enantiomer ones (2a/2b, 4a/4b and 6a/6b) and four optical pure ones (1, 3, 5 and 7), as well as five known structural analogues (8-12), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray diffraction, 13C NMR calculation and DP4+ probability analyses, as well as the comparison of the experimental electronic circular dichroism (ECD) data. Structurally, compound 1 featured an unprecedented chromone-derived sulfonamide tailored by two isoleucine-derived δ-hydroxy-3-methylpentenoic acids via the acylamide and NO bonds, respectively; compound 2 represented the first example of enantiomeric chromone derivative bearing a unique spiro-[3.3]alkane ring system; compound 3 featured a decane alkyl side chain that formed an undescribed five-membered lactone ring between C-7' and C-10'; compound 4 contained an unexpected highly oxidized five-membered carbocyclic system featuring rare adjacent keto groups; compound 7 featured a rare methylsulfonyl moiety. In addition, compound 10 showed a significant inhibition towards SW620/AD300 cells with an IC50 value of PTX significantly decreased from 4.09 µM to 120 nM, and a further study uncovered that compound 10 could obviously reverse the MDR of SW620/AD300 cells.

A Novel 3-Benzyloxychromone From Celastrus orbiculatus Thunb. Exhibits Anticancer Effects on Non-Small Cell Lung Cancer Cells via GSK-3ß-Dependent c-Jun/ATF2 Pathway.

Celastrus orbiculatus Thunb. is a vine used as a traditional Chinese medicinal herb. In this study, we focused on the anticancer cytotoxicity and underlying mechanism of previously unreported 3-oxygen-substituted isoflavone analogue (3-benzyloxychromone, 3-Boc) from the herb. Initially, we established cell line-derived xenograft mouse model using H1299 non-small cell lung cancer (NSCLC) cells and found that the ethanol crude extracts of the stem part of C. orbiculatus (200 mg/kg) could substantially suppress the growth of xenograft tumors in athymic nu/nu mice. We compared 3-Boc with three other flavonoid analogues isolated from the stem part of C. orbiculatus. Among these, 3-Boc showed the most potent cytotoxicity against H1299 and H1975 NSCLC cells. Colony formation, EdU incorporation and Annexin V-FITC/PI apoptosis assays demonstrated that 3-Boc induced growth inhibition primarily by inhibiting DNA replication and inducing apoptotic death of NSCLC cells. Structure-based target prediction and MD simulation suggested that 3-Boc potentially suppressed the activity of glycogen synthase kinase-3ß (GSK-3ß) by interacting with the ATP-binding site. Western blot analysis indicated that 3-Boc triggered the phosphorylation of Serine 21 of GSK-3α or Serine 9 of GSK-3ß in a time- and dose-dependent manner. To investigate the dependency of GSK-3ß, we established GSK-3ß knockout in H1299 cells. Depletion of GSK-3ß enhanced 3-Boc-induced cytotoxicity compared with wild-type counterparts through activated c-Jun/ATF2 signaling pathway. Altogether, our study highlights the anticancer potential of C. orbiculatus and the discovery of novel 3-oxygen-substituted chromone from the herb, which may have important implications for screening promising modulators of GSK-3ß and related signaling pathways in the treatment of cancer.

Discovery of a Novel Chromone Enantiomer and the Precursors of Nonactic Acid from the Coral-Reef-Derived Streptomyces sp. SCSIO 66814.

Three pairs of enantiomers (1-3)-the new 12R-aloesol (1a) and two new fatty acids (2 and 3)-and one new natural product (4) together three known compounds (5-7) were isolated from a coral-reef-derived Streptomyces sp. SCSIO 66814. Their structures were determined through extensive spectroscopic analysis, chiral analysis, and single-crystal X-ray diffraction data. Compounds 2 and 3 were presumed to be intermediates for further generating homononactic acid (5) and nonactic acid, and the latter two molecules were able to act as precursors to form macrotetrolides with remarkable biological activity. The isolation of related precursors, compounds 2-5, provided more evidence to support the proposal of a plausible biosynthetic pathway for nonactic acid and its homologs. Additionally, (+)-1 exhibited a weak activity against DPPH radicals.

New Fusarochromanone Derivatives from the Marine Fungus Fusarium equiseti UBOCC-A-117302.

Two new fusarochromanone derivatives, deacetylfusarochromene (1) and deacetamidofusarochrom-2',3-diene (2), along with the previously reported metabolites fusarochromanone TDP-2 (3), fusarochromene (4), 2,2-dimethyl-5-amino-6-(2'E-ene-4'-hydroxylbutyryl)-4-chromone (5), fusarochromanone (6), (-)-chrysogine (7), and equisetin (8), were isolated from the marine fungus Fusarium equiseti UBOCC-A-117302. The structures of the compounds were determined by extensive spectrometric (HRMS) and spectroscopic (1D and 2D NMR) analyses, as well as specific rotation. Among them, 2 and 5 showed inhibition of three protein kinases with IC50 values ranging from 1.42 to 25.48 µM. Cytotoxicity and antimicrobial activity of all isolated compounds were also evaluated. Six fusarochromanone derivatives (1-6) exhibited diverse activities against three cell lines, RPE-1, HCT-116, and U2OS (IC50 values ranging from 0.058 to 84.380 µM). Equisetin (8) showed bactericidal activities against Bacillus cereus and Listeria monocytogenes (MBC values of 7.8 and 31.25 µM, respectively), and bacteriostatic activity against Enterococcus faecalis (MIC value of 31.25 µM). Compounds 2 and 4 showed bacteriostatic activities against Listeria monocytogenes (MIC of 125 µM).

Amycolachromones A-F, Isolated from a Streptomycin-Resistant Strain of the Deep-Sea Marine Actinomycete Amycolatopsis sp. WP1.

In this study, a detailed chemical investigation of a streptomycin-resistant strain of the deep-sea marine, actinomycete Amycolatopsis sp. WP1, yielded six novel amycolachromones A-F (1-6), together with five known analogues (7-11). Amycolachromones A-B (1-2) possessed unique dimer skeletons. The structures and relative configurations of compounds 1-11 were elucidated by extensive spectroscopic data analyses combined with X-ray crystal diffraction analysis. Plausible biogenetic pathways of amycolachromones A-F were also proposed.

Aurasperone A Inhibits SARS CoV-2 In Vitro: An Integrated In Vitro and In Silico Study.

Several natural products recovered from a marine-derived Aspergillus niger were tested for their inhibitory activity against SARS CoV-2 in vitro. Aurasperone A (3) was found to inhibit SARS CoV-2 efficiently (IC50 = 12.25 µM) with comparable activity with the positive control remdesivir (IC50 = 10.11 µM). Aurasperone A exerted minimal cytotoxicity on Vero E6 cells (CC50 = 32.36 mM, SI = 2641.5) and it was found to be much safer than remdesivir (CC50 = 415.22 µM, SI = 41.07). To putatively highlight its molecular target, aurasperone A was subjected to molecular docking against several key-viral protein targets followed by a series of molecular dynamics-based in silico experiments that suggested Mpro to be its primary viral protein target. More potent anti-SARS CoV-2 Mpro inhibitors can be developed according to our findings presented in the present investigation.

Induction of Isochromanones by Co-Cultivation of the Marine Fungus Cosmospora sp. and the Phytopathogen Magnaporthe oryzae.

Microbial co-cultivation is a promising approach for the activation of biosynthetic gene clusters (BGCs) that remain transcriptionally silent under artificial culture conditions. As part of our project aiming at the discovery of marine-derived fungal agrochemicals, we previously used four phytopathogens as model competitors in the co-cultivation of 21 marine fungal strains. Based on comparative untargeted metabolomics analyses and anti-phytopathogenic activities of the co-cultures, we selected the co-culture of marine Cosmospora sp. with the phytopathogen Magnaporthe oryzae for in-depth chemical studies. UPLC-MS/MS-based molecular networking (MN) of the co-culture extract revealed an enhanced diversity of compounds in several molecular families, including isochromanones, specifically induced in the co-culture. Large scale co-cultivation of Cosmospora sp. and M. oryzae resulted in the isolation of five isochromanones from the whole co-culture extract, namely the known soudanones A, E, D (1-3) and their two new derivatives, soudanones H-I (4-5), the known isochromans, pseudoanguillosporins A and B (6, 7), naphtho-γ-pyrones, cephalochromin and ustilaginoidin G (8, 9), and ergosterol (10). Their structures were established by NMR, HR-ESIMS, FT-IR, electronic circular dichroism (ECD) spectroscopy, polarimetry ([α]D), and Mosher's ester reaction. Bioactivity assays revealed antimicrobial activity of compounds 2 and 3 against the phytopathogens M. oryzae and Phytophthora infestans, while pseudoanguillosporin A (6) showed the broadest and strongest anti-phytopathogenic activity against Pseudomonas syringae, Xanthomonas campestris, M. oryzae and P. infestans. This is the first study assessing the anti-phytopathogenic activities of soudanones.

Chromene and chromone derivatives as liver X receptors modulators from a marine-derived Pestalotiopsis neglecta fungus.

Four new chromene derivatives, pestalotiochromenoic acids A - D (1, 2, 4, and 5), and two new chromone derivatives, pestalotiochromones A and B (6 and 7), were obtained from the marine alga-derived fungus Pestalotiopsis neglecta SCSIO41403, as well as a reported derivate named piperochromenoic acid (3) with its configuration determined for the first time. Their structures were determined by detailed nuclear magnetic resonance (NMR) and mass spectroscopic analyses, while the absolute configurations were established by theoretical NMR and electronic circular dichroism (ECD) calculation, including Mo2(OAc)4-induced ECD experiments. Those chromene and chromone derivatives displayed weak cytotoxicity, but showed obvious liver X receptors (LXRs) modulatory activities, by in vitro tests on the expression of LXRα, LXRß and theirtarget gene ABCA1, as well as in silico docking analysis. Moreover, the high binding affinities between pestalotiochromone A (6) and LXRα, revealed by surface plasmon resonance (SPR) with the dissociation equilibrium constant (KD) value of 6.2 µM, demonstrated 6 could act as a new potential LXR agonist.

Synthesis, biological evaluation, and molecular docking study of some new rohitukine analogs as protein tyrosine phosphatase 1B inhibitors.

Rohitukine (RH) was extracted from the stem bark of Dysoxylum binectariferum Hook. It was derivatized to different arylsulphanmides by treating with the corresponding aryl sulphonyl chlorides. These derivatives were tested in-vitro on protein tyrosine phosphatase 1B (PTP1B) inhibition. Among these the active compounds K2, K3, K5, and K8 significantly inhibited the PTP1B by 51.3%, 65.6%, 71.9%, and 55.9% respectively at 10 µg/ml, the results were also supported by in-silico docking experiments. The most potent compound K5 was analyzed for antidiabetic and antidyslipidemic activity in vivo. It showed a marked reduction in blood glucose level (random and fasting) and serum insulin level in db/db mice. It improved glucose intolerance as ascertained by the oral glucose tolerance test (OGTT). These NCEs (New Chemical Entities) also lowered cholesterol and triglyceride profiles while improved high-density lipoprotein cholesterol in db/db mice. The K5 was further evaluated for antiadipogenic activity on MDI (Methylisobutylxanthine, dexamethasone, and insulin)-induced adipogenesis. where it significantly inhibited MDI-induced adipogenesis in 3 T3-L1 preadipocytes, at 10 µM and 20 µM concentration. These results were compared with the parent compound RH which inhibited 35% and 45% lipid accumulation while the RH analog K5 inhibited the lipid accumulation by 41% and 51% at 10 and 20 µM concentration, respectively. These results well corroborated with in-silico studies.

Anti-proliferative and anti-inflammatory prenylated isoflavones and coumaronochromones from the fruits of Ficus altissima.

Ficus altissima, an evergreen arbor belonging to the Moraceae family, is mainly cultivated in the tropics and subtropics of South and Southeast Asia with the characteristic of exuberant vitality and luxuriant foliage. In this article, four new prenylated isoflavones (1-4), along with ten previously described isoflavones (5-14) and two known prenylated coumaronochromones (15 and 16) were firstly obtained from the fruits of F. altissima. Their structures were identified by various spectroscopic techniques including specific optical rotation, HR-ESI-MS and NMR. The isolated products were evaluated for their anti-proliferative activities against three human tumor cell lines (HepG2, MCF-7 and MDA-MB-231) through MTT assay. Compounds 2, 3 and 16 exhibited obvious anti-proliferative activities against MDA-MB-231 cell line and compounds 3, 13 and 16 showed effective cytotoxic effects on HepG2 cell line in a concentration-dependent manner, as verified by the colony formation assay, cell and nucleus morphological assessment and apoptosis assay. Meanwhile, compounds 5 and 12 exhibited significant inhibition activities on NO production in LPS-stimulated RAW 264.7 cell line compared with positive control indometacin. The phytochemical investigation of the fruits of F. altissima in this study could provide the evidence for the discovery of lead compounds.

Separation of three chromones from Saposhnikovia divaricata using macroporous resins followed by preparative high-performance liquid chromatography.

Prim-O-glucosylcimifugin, cimifugin, and 5-O-methylvisamminoside are three major chromone derivatives of Saposhnikovia divaricata that have many pharmacological activities, such as anti-inflammatory and antitumor activities. In the present work, an effective method for the simultaneous separation of prim-O-glucosylcimifugin, cimifugin, and 5-O-methylvisamminoside with high purities was established using HPD-300 resin coupled with preparative high-performance liquid chromatography. The adsorption kinetics curves of the three compounds on the HPD-300 resin were studied and found to fit well according to the pseudo-second-order equation. The adsorption isotherm results indicated that the adsorption process of the three compounds was exothermic. After a one-run treatment with the resin, the contents of prim-O-glucosylcimifugin, cimifugin, and 5-O-methylvisamminoside increased from 0.29, 0.06, and 0.37% to 13.07, 2.83, and 16.91% with recovery yields of 76.38, 78.25, and 76.73%, respectively. Finally, the purities of the three compounds were found to reach more than 95% after further separation using preparative high-performance liquid chromatography. The method developed in this study was effective and could simultaneously separate three chromones from Saposhnikovia divaricate. The experimental results also showed that the HPD-300 resin is suitable for the separation of chromone derivatives.

Four New Chromones from the Endophytic Fungus Phomopsis asparagi DHS-48 Isolated from the Chinese Mangrove Plant Rhizophora mangle.

Four new chromones, phomochromenones D-G (1-4), along with four known analogues, diaporchromone A (5), diaporchromanone C (6), diaporchromanone D (7), and phomochromenone C (8), were isolated from the culture of Phomopsis asparagi DHS-48 from Chinese mangrove Rhizophora mangle. Their structures were elucidated on the basis of comprehensive spectroscopic analysis. The absolute configurations of 1 and 4 were assigned on the basis of experimental and calculated electronic circular dichroism (ECD) data, and those of enantiomers 2 and 3 were determined by a modified Mosher's method and basic hydrolysis. To the best of our knowledge, phomochromenones D-F (1-4) possessing a 3-substituted-chroman-4-one skeleton are rarely found in natural sources. Diaporchromone A (5) showed moderate to weak immunosuppressive activity against T and/or B lymphocyte cells with IC50 of 34 µM and 117 µM.

Three New 2,2'-Difurylketone Derivatives and Two New Chromones from the Rehmanniae Radix Praeparata.

Rehmanniae Radix Praeparata is the processed products of the root of Rehmannia glutinosa. It has been used as a Traditional Chinese Medicine for thousands of years, and it has been found to possess widely pharmacological activities. In this study, three new 2,2'-difurylketone derivatives (rehmanniaeketone A-C) and two new chromones [3,8-dihydroxy-2-(2-hydroxyethyl)chromone and 3,8-dihydroxy-2-[(2-O-α-D-galactopyranosyloxy)ethyl]chromone] were isolated from the Rehmanniae Radix Praeparata. Furthermore all of the compounds were subjected to cytotoxic testing against the human lung carcinoma A549 cells. The cytotoxic results showed that rehmanniaeketone B and rehmanniaeketone C exhibited more stronger inhibition effects on the cell activity of A549 cells with the IC50 5.23 µM and 2.05 µM than other compounds. And 3,8-dihydroxy-2-(2-hydroxyethyl)chromone exhibited moderately inhibitory activity with the IC50 61 µM. Rehmanniaeketone A and 3,8-dihydroxy-2-[(2-O-α-D-galactopyranosyloxy]chromone showed no inhibitory effects.

Matteucinol, isolated from Miconia chamissois, induces apoptosis in human glioblastoma lines via the intrinsic pathway and inhibits angiogenesis and tumor growth in vivo.

Gliomas account for nearly 70% of the central nervous system tumors and present a median survival of approximately 12-17 months. Studies have shown that administration of novel natural antineoplastic agents is been highly effective for treating gliomas. This study was conducted to investigate the antitumor potential (in vitro and in vivo) of Miconia chamissois Naudin for treating glioblastomas. We investigated the cytotoxicity of the chloroform partition and its sub-fraction in glioblastoma cell lines (GAMG and U251MG) and one normal cell line of astrocytes. The fraction showed cytotoxicity and was selective for tumor cells. Characterization of this fraction revealed a single compound, Matteucinol, which was first identified in the species M. chamissois. Matteucinol promoted cell death via intrinsic apoptosis in the adult glioblastoma lines. In addition, Matteucinol significantly reduced the migration, invasion, and clonogenicity of the tumor cells. Notably, it also reduced tumor growth and angiogenesis in vivo. Moreover, this agent showed synergistic effects with temozolomide, a chemotherapeutic agent commonly used in clinical practice. Our study demonstrates that Matteucinol from M chamissois is a promising compound for the treatment of glioblastomas and may be used along with the existing chemotherapeutic agents for more effective treatment.

Talauxins: Hybrid Phenalenone Dimers from Talaromyces stipitatus.

Cultivation and extraction of the fungus Talaromyces stipitatus led to the isolation of five new oxyphenalenone-amino acid hybrids, which were named talauxins E, Q, V, L, and I based on the corresponding one-letter amino acid codes, along with their putative biosynthetic precursor, duclauxin. The rapid reaction of duclauxin with amino acids to produce talauxins was demonstrated in vitro and exploited to generate a small library of natural and unnatural talauxins. Talauxin V was shown to undergo spontaneous elimination of methyl acetate to yield the corresponding neoclauxin scaffold. This process was modeled using density functional theory calculations, revealing a dramatic change in conformation resulting from the syn elimination of methyl acetate.

Four New Chromone Derivatives from Colletotrichum gloeosporioides.

Four previously unreported chromones, 5-hydroxy-2-(hydroxymethyl)-8-methoxy-4H-chromen-4-one (1), (5R,7S)-5,7-dihydroxy-2-propyl-5,6,7,8-tetrahydro-4H-chromen-4-one (2), (5R,7S)-5,7-dihydroxy-2-methyl-5,6,7,8-tetrahydro-4H-chromen-4-one (3), and (5R,7S)-5,7-dihydroxy-2-[(E)-prop-1-en-1-yl]-5,6,7,8-tetrahydro-4H-chromen-4-one (4), as well as one known analogue 5-hydroxy-2-methyl-4H-chromen-4-one (5) were isolated from the fermentation broth of the endophytic fungus Colletotrichum gloeosporioides derived from the mangrove Ceriops tagal. Their structures were elucidated based on extensive spectroscopic analyses. The absolute configurations of 2-4 were determined by comparison the experimental and calculated electronic circular dichroism (ECD) spectra. Compound 2 showed cytotoxic activity against A549 cell line with the IC50 value of 0.094 mm.

Adiponectin-Secretion-Promoting Phenylethylchromones from the Agarwood of Aquilaria malaccensis.

The therapeutic potential of adiponectin regulation has received interest because of its association with diverse human disease conditions, such as diabetes, obesity, atherosclerosis, and cancer. Phenylethylchromone derivatives from Aquilaria malaccensis-derived agarwood promoted adiponectin secretion during adipogenesis in human bone marrow mesenchymal stem cells, and 5,6-dihydroxy-2-(2-phenylethyl)chromone (1) was identified as a new chromone derivative. A target identification study with the most potent adiponectin-secretion-promoting phenylethylchromones, 6-methoxy-2-(2-phenylethyl)chromone (3) and 7-methoxy-2-(2-phenylethyl)chromone (4), showed that they are PPARγ partial agonists. Therefore, the diverse therapeutic effects of agarwood are associated with a PPARγ-mediated adiponectin-secretion-promoting mechanism.

Sesquiterpenoids and 2-(2-phenylethyl)chromones respectively acting as α-glucosidase and tyrosinase inhibitors from agarwood of an Aquilaria plant.

The ethyl ether extract of agarwood from an Aquilaria plant afforded six new sesquiterpenoids, Agarozizanol A - F (1-6), together with four known sesquiterpenoids and six known 2-(2-phenylethyl)chromones. Their structures were elucidated via detailed spectroscopic analysis, X-ray diffraction, and comparisons with the published data. All the isolates were evaluated for the α-glucosidase and tyrosinase inhibitory activities in vitro. Compounds 5, 7, 8, and 10 showed significant inhibition of α-glucosidase with IC50 values ranging between 112.3 ± 4.5 and 524.5 ± 2.7 µM (acarbose, 743. 4 ± 3.3 µM). Compounds 13 and 14 exhibited tyrosinase inhibitory effect with IC50 values of 89.0 ± 1.7 and 51.5 ± 0.6 µM, respectively (kojic acid, 46.1 ± 1.3). In the kinetic studies, compounds 5 and 14 were found to be uncompetitive inhibitors for α-glucosidase and mixed type inhibitors for tyrosinase, respectively. Furthermore, molecular docking simulations revealed the binding sites and interactions of the most active compounds with α-glucosidase and tyrosinase.

A New Macrodiolide and Two New Polycyclic Chromones from the Fungus Penicillium sp. SCSIO041218.

A new macrodiolide, mangrovlide A (1) and two new polycyclic chromones, penixanthones C (2) and D (3), as well as four other known compounds (4-7), have been isolated from the mangrove sediment derived fungus Penicillium sp. SCSIO041218, cultured in the 0.25% NaCl rice substrate. The structures of the new compounds were determined by analysis of the NMR and MS spectroscopic data. Compound 1 possesses a 10-membered macrodiolide unit, while 2 and 3 are chromones with an unprecedented 6/6/6/5 polycyclic skeleton. Compounds 1-7 were evaluated for their cytotoxicities, while all the compounds displayed weak or no activity.

Rapid identification of antimicrometastases drugs using integrated model systems with two dimensional monolayer, three dimensional spheroids, and zebrafish xenotransplantation tumors.

Treating systemic metastases at the micrometastatic stage is a potential strategy to inhibit cancer metastasis. This study aims to establish an apoptosis sensor-based platform for rapid, effective, and noninvasive identification of drugs that can inhibit the proliferation of micrometastatic cancer cells. We stably transfected the plasmid DNA encoding the fluorescence resonance energy transfer-based caspase-3 sensor into highly metastatic melanoma B16F10 cells. The resulting B16F10-C3 cells were applied for screening of antiproliferative and proapoptotic drugs in two-dimensional (2D) monolayer, three-dimensional (3D) spheroids, and zebrafish xenotransplantation tumors. All studies were conducted in 96-well plates in a high throughput manner. Fourteen compounds including six chemotherapeutic drugs and eight kinase inhibitors were tested. Thirteen compounds failed the tests due to: Drug resistance, low efficacy, poor pharmacokinetic profile, and/or high side effects to zebrafish. The only compound that passed all tests was pan-phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, which inhibited the proliferation of B16F10-C3 cells in both 2D and 3D cultures. More important, it significantly reduced the xenograft tumor size in zebrafish by decreasing the viability of metastatic cancer cells. Our study suggests that the PI3K/AKT pathway is a potential therapeutic target for the reactivation of tumor dormancy and proliferation of micrometastases. Moreover, this integrated approach is effective for rapid identification of systemic antimetastases drugs.