Two new benzophenone glycosides, hypersens A and B, along with four known compounds, (S)-(+)-5,7-dihydroxy-2-(1-methylpropyl) chromone (3), 5,7-dihydroxy-2-isopropylchromone (4), urachromone B (5), and 3-8'' bisapigenin (6), were isolated from Hypericum seniawinii. The structures of new compounds (1 and 2) were elucidated according to comprehensive spectroscopic data analyses. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) calculations. All isolated compounds were evaluated for their neuroprotective effect using corticosterone-induced PC12 cell injury. In addition, compounds 1-6 were evaluated for their anti-inflammatory activity in lipopolysaccharide-induced RAW 264.7 cells. Compound 6 was a biflavonoid and significantly inhibited the production of nitric oxide with an IC50 value of 11.48 ± 1.23 μM.

Chromones (sodium cromoglycate and sodium nedocromil) block cell swelling-activated Cl- channels in NIH-3T3 fibroblasts and endothelial cells. This has led to hypothesize that cell volume regulation might be involved in asthma pathogenesis. Using whole-cell patch-clamp experiments, we studied the effect of chromones on volume-sensitive Cl- currents in transformed human tracheal epithelial cells (9HTEo-) and in primary cultures of human bronchial epithelial cells (BE). Cl- currents activated by hypotonic shock were poorly blocked by extracellular nedocromil or cromoglycate. The block was voltage-dependent since it was observed only at positive membrane potentials. At the concentration of 5 mM, the current inhibition by both chromones at +80 mV was about 40% for 9HTEo- and only 20% for BE. Intracellular application of chromones elicited a voltage-independent inhibition in 9HTEo- cells. Under this condition, volume-sensitive Cl- currents were reduced at all membrane potentials (60 and 45% inhibition by 2 mM nedocromil and cromoglycate respectively). In contrast intracellular chromones were ineffective in BE cells. The relative refractoriness to chromones, in contrast with the high sensitivity shown by other Cl- channels, suggests that the epithelial volume-sensitive Cl- channel is not involved in asthma.

Vegetative but not reproductive stage of Saposhnikovia divaricate (Turxz.) schischk possesses pharmacological activities. However, our recent study showed that reproductive S. divaricate supplemented with polysaccharide showed evidently elevated pharmacological activities and increased cimifugin content in rat serum. The aims of present study were to assess the influence of polysaccharides on the chromones pharmacological activities in Radix Saposhnikoviae (RS), the dried root of vegetative stage of S. divaricate, and to explore the underlying mechanisms. Only cimifugin was detected in the plasma of chromone treated animals and RS polysaccharide significantly increased the plasma content of cimifugin. It was shown that neither cimifugin absorption nor glycoside components transformation in simulated digestive fluid was affected by RS polysaccharide. However, a significant promotion of transformation of cimifugin to more stable prime-O-glucosylcimifugin (PGCN) by RS polysaccharide, and a protective effect of polysaccharide on chromone components were observed in small intestine solutions. Meanwhile, RS polysaccharide produced a significant elevation of cimifugin and PGCN concentration in vivo. Based on these findings, we concluded that RS polysaccharide could greatly increase the content of cimifugin, which might be related to its degradation-proof effect on cimifugin, via transforming cimifugin to comparatively more stable PGCN and spatial structure protection.

Three gold(I) complexes of alkynyl chromones were synthesized and characterized. The single-crystal X-ray structure analysis of a dinuclear compound and of a flavone derivative exhibit a typical d10 gold(I)-alkynyl linear arrangement. All complexes were evaluated as anticancer and antibacterial agents against four human cancer cell lines and four pathogenic bacterial strains. All compounds show antiproliferative activity at lower micromolar range concentrations. Complex 4 showed a broad activity profile, being more active than the reference drug auranofin against HepG2, MCF-7 and CCRF-CEM cancer cells. The cellular uptake into MCF-7 cells of the investigated complexes was measured by atomic absorption spectroscopy (AAS). These measurements showed a positive correlation between an increased cellular gold content and the incubation time of the complexes. Unexpectedly an opposite effect was observed for the most active compound. Biological assays revealed various molecular mechanisms for these compounds, comprising: (i) thioredoxin reductase (TrxR) inhibition, (ii) caspases-9 and -3 activation; (iii) DNA damaging activity and (iv) cell cycle disturbance. The gold(I) complexes were also bactericidal against Gram-positive methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) bacterial strains, while showing no activity against the Gram-negative Escherichia coli bacterial strain.

The persistence of Candida infections is due to its ability to form biofilms that enable it to resist antifungals and host immune systems. Hence, inhibitions of the biofilm formation and virulence characteristics of Candida sp. provide potential means of addressing these infections. Among various chromone derivatives tested, four chromone-3-carbonitriles showed antifungal, antibiofilm, and antivirulence activities against several Candida species. Their mode of action has been partially revealed, and their toxicity is reported here using nematode and plant models.

Current research is based on the identification of novel inhibitors of α-amylase enzyme. For that purpose, new hybrid molecules of hydrazinyl thiazole substituted chromones 5-27 were synthesized by multi-step reaction and fully characterized by various spectroscopic techniques such as EI-MS, HREI-MS, 1H-NMR and 13C-NMR. Stereochemistry of the iminic bond was confirmed by NOESY analysis of a representative molecule. All compounds 5-27 along with their intervening intermediates 1-4, were screened for in vitro α-amylase inhibitory, DPPH and ABTS radical scavenging activities. All compounds showed good inhibition potential in the range of IC50 = 2.186-3.405 µM as compared to standard acarbose having IC50 value of 1.9 ± 0.07 µM. It is worth mentioning that compounds were also demonstrated good DPPH (IC50 = 0.09-2.233 µM) and ABTS (IC50 = 0.584-3.738 µM) radical scavenging activities as compared to standard ascorbic acid having IC50 = 0.33 ± 0.18 µM for DPPH and IC50 = 0.53 ± 0.3 µM for ABTS radical scavenging activities. In addition to that cytotoxicity of the compounds were checked on NIH-3T3 mouse fibroblast cell line and found to be non-toxic. In silico studies were performed to rationalize the binding mode of compounds (ligands) with the active site of α-amylase enzyme.

Three new and rare chromones, named epiremisporine B (2), epiremisporine B1 (3) and isoconiochaetone C (4), along with three known remisporine B (1), coniochaetone A (5) and methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (6) were isolated from a mutant from the diethyl sulfate (DES) mutagenesis of a marine-derived Penicillium purpurogenum G59. The structures of 2-4 including the absolute configurations were determined by spectroscopic methods, especially by NMR analysis and electronic circular dichroism (ECD) experiments in conjunction with calculations. The absolute configuration of the known remisporine B (1) was determined for the first time. Compounds 2 and 3 have a rare feature that has only been reported in one example so far. The compounds 1-6 were evaluated for their cytotoxicity against several human cancer cell lines. The present work explored the great potential of our previous DES mutagenesis strategy for activating silent fungal pathways, which has accelerated the discovery of new bioactive compounds.

Five new chromone derivatives, arthones A⁻E (1⁻5), together with eight known biogenetically related cometabolites (6⁻13), were isolated from a deep-sea-derived fungus Arthrinium sp. UJNMF0008. Their structures were assigned by detailed analyses of spectroscopic data, while the absolute configurations of 1 and 5 were established by electronic circular dichroism (ECD) calculations and that of 2 was determined by modified Mosher ester method. Compounds 3 and 8 exhibited potent antioxidant property with DPPH and ABTS radical scavenging activities, with IC50 values ranging from 16.9 to 18.7 μM. Meanwhile, no compounds indicated obvious bioactivity in our antimicrobial and anti-inflammatory assays at 50.0 μM.

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.

We investigated the biological activity of a series of substituted chromeno[3,2-c]pyridines, including compounds previously synthesized by our group and novel compounds whose syntheses are reported here. Tandem transformation of their tetrahydropyridine ring under the action of activated alkynes yielding 2-vinylsubstituted chromones was used to prepare nitrogen-containing derivatives of a biologically active chromone system. The inhibitory activity of these chromone derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) was investigated using the methods of enzyme kinetics and molecular docking. Antioxidant (antiradical) activity of the compounds was assessed in the ABTS assay. The results demonstrated that a subset of the studied chromone derivatives selectively inhibit BChE but do not exhibit antiradical activity. In addition, the results of molecular docking effectively explained the observed features in the efficacy, selectivity, and mechanism of BChE inhibition by the chromone derivatives.

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.

The straightforward syntheses of four new ferrocenyl and dicobalt hexacarbonyl chromones are presented. The redox behavior of the novel metallo-chromones has been examined by cyclic voltammetry (CV), revealing a reversible behavior of the ferrocenyl groups, while the dicobalt hexacarbonyl derivatives show irreversible oxidation. The anticancer activity of the products has been evaluated against hepatocellular carcinoma (Hep G2), ER+ (MCF-7) and ER- (MDA-MB-231) breast adenocarcinoma, and leukemic (CCRF-CEM) human cancer cell lines. The mechanism of action for the most active complexes has been investigated and it seems to involve oxidative stress and apoptosis induction. Moreover, the results show that the investigated metallo-chromones generate damage to DNA and arrest the cell cycle in G2/M phase.

Pimenta dioica (L.) Merr. (Myrtaceae) is used in Costa Rican traditional medicine for women's health. Our previous work showed that P. dioica extracts were oestrogenic.

2-(2-Phenylethyl)chromones (PECs) are the principal constituents contributing to the distinctive fragrance of agarwood. How PECs are biosynthesized is currently unknown. In this work, we describe a diarylpentanoid-producing polyketide synthase (PECPS) identified from Aquilaria sinensis. Through biotransformation experiments using fluorine-labeled substrate, transient expression of PECPS in Nicotiana benthamiana, and knockdown of PECPS expression in A. sinensis calli, we demonstrate that the C6-C5-C6 scaffold of diarylpentanoid is the common precursor of PECs, and PECPS plays a crucial role in PECs biosynthesis. Crystal structure (1.98 Å) analyses and site-directed mutagenesis reveal that, due to its small active site cavity (247 Å3), PECPS employs a one-pot formation mechanism including a "diketide-CoA intermediate-released" step for the formation of the C6-C5-C6 scaffold. The identification of PECPS, the pivotal enzyme of PECs biosynthesis, provides insight into not only the feasibility of overproduction of pharmaceutically important PECs using metabolic engineering approaches, but also further exploration of how agarwood is formed.

A mangrove endophytic fungus Phomopsis asparagi DHS-48 was found to be particularly productive with regard to the accumulation of substantial new compounds in our previous study. In order to explore its potential to produce more unobserved secondary metabolites, epigenetic manipulation was used on this fungus to activate cryptic or silent genes by using the histone deacetylase (HDAC) inhibitor sodium butyrate and the DNA methyltransferase (DNMT) inhibitor 5-azacytidine (5-Aza). Based on colony growth, dry biomass, HPLC, and 1H NMR analyses, the fungal chemical diversity profile was significantly changed compared with the control. Two new compounds, named phaseolorin J (1) and phomoparagin D (5), along with three known chromones (2-4) and six known cytochalasins (6-11), were isolated from the culture treated with sodium butyrate. Their structures, including their absolute configurations, were elucidated using a combination of detailed HRESIMS, NMR, and ECD and 13C NMR calculations. The immunosuppressive and cytotoxic activities of all isolated compounds were evaluated. Compounds 1 and 8 moderately inhibited the proliferation of ConA (concanavalin A)-induced T and LPS (lipopolysaccharide)-induced B murine spleen lymphocytes. Compound 5 exhibited significant in vitro cytotoxicity against the tested human cancer cell lines Hela and HepG2, which was comparative to the positive control adriamycin and fluorouracil. Our finding demonstrated that epigenetic manipulation should be an efficient strategy for the induction of new metabolites from mangrove endophytic fungi.

A method, quantitative analysis of multicomponents by single marker (QAMS), was established and fully verified based on high-performance liquid chromatography (HPLC) for simultaneous determination of six chromone indicators of Saposhnikoviae Radix (SR). In the present study, cimifugin (C), 5-O-methylvisamminol (V), hamaudol (H), and their corresponding glycosides, prim-O-glucosylcimifugin (GC), 4'-O-β-D-glucosyl-5-O-methylvisamminol (GV), and sec-O-glucosylhamaudol (GH), were selected as bioactive constituents and indicators for the quality evaluation of SR. GV was chosen as the unique reference standard, and relative correction factors (RCF) between GV and the other five chromones were calculated. The feasibility of QAMS for the analysis of chromones was investigated by comparing with the traditional external standard method (ESM). Furthermore, the method was proven to have accuracy (96.98%-102.50%), repeatability (RSD <3%), stability (RSD <3%), precision (RSD <3%), and desirable linearity (R 2 ≧0.9999). Subsequently, 55 batches of commercial SR from different regions were determined by QAMS, and their contents were analyzed by principal component analysis (PCA), correlation analysis, and hierarchical cluster analysis (HCA), respectively. Based on the results, a more refined quality standard of commercial SR was proposed: SR was qualified when the total contents of six chromones were greater than 3 mg·g-1. Furthermore, SR could initially be regarded as a superior medicine when it satisfied both conditions at the same time: the total content of GC, C, GV, V, GH, and H was greater than 8 mg·g-1, and the proportion of the total content of C, V, and H was greater than 10%. This study demonstrated that the quality of SR could be successfully evaluated by the developed QAMS method; meanwhile, valuable information was provided for improving the quality standard of SR.

Saposhnikovia divaricata (family Apiaceae) a traditional medicinal plant distributed in many provinces of China, is well known for the pharmaceutical value and has been used for rheumatic arthritis, and anxiety in children. Antiviral, antioxidant and antiproliferative activities were also mentioned. The application of this plant are recorded in the Chinese Medicine (CM) classical text the Shen Nong's Materia Medica (Shen Nong Ben Cao Jing). In this monograph S. divaricata (syn Radix Ledebouriella divaricata) is graded as a premium-grade herb, with their broad-spectrum of therapeutic applications for the treatment of cough, common cold, arthralgia, as well as in rheumatic disorders.

The one-pot regioselective and catalytic synthesis of bioactive chromones and flavones was achieved via phosphine-free cyclocarbonylative Sonogashira coupling reactions of 2-iodophenols with aryl alkynes, alkyl alkynes, and dialkynes. The reactions are catalyzed by new dibromidobis(NHC)palladium(II) complexes. The new bridged N,N'-substituted benzimidazolium salts (L1, L2, and L3) and their palladium complexes C1, C2, and C3 were designed, prepared, and fully characterized using different physical and spectroscopic techniques. The molecular structures of complexes C1 and C3 were determined by single-crystal X-ray diffraction analysis. They showed a distorted square planar geometry, where the Pd(II) ion is bonded to the carbon atoms of two cis NHC carbene ligands and two cis bromido anions. These complexes displayed a high catalytic activity in cyclocarbonylative Sonogashira coupling reactions with low catalyst loadings. The regioselectivity of these reactions was controlled by using diethylamine as the base and DMF as the solvent.

The successful launch of icaritin, a therapeutic drug for liver cancer derived from Epimedium brevicornu, has provided new impetus for the development of prenylated flavonoids in the field of oncology. Flemingia macrophylla is reported to contain characteristic prenylated flavonoids which can regulate the p53 protein. We aimed to isolate these constituents and conduct activity evaluation, structure-activity relationship, and mechanism studies to provide candidate compounds for antitumor drug development.

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.