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Further study on the chemical constituents present in the fruit of Averrhoa carambola L. (Oxalidaceae), commonly called star fruit or carambola, led to the isolation of six new dihydrochalcone C -glycosides, carambolasides E∼J ( 1 ∼ 6 ). Their structures were determined by spectroscopic and chemical methods, including low temperature nuclear magnetic resonance (NMR). Compounds 1 ∼ 6 and two alkaline hydrolysates, 5a and 6a , exhibited more potent 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) radical cation (ABTS + ) scavenging activity with IC 50 values ranging from 4.52 to 2.54 μM than l -ascorbic acid (14.21 μM). However, they were inactive in scavenging 1,1-diphenyl-2-picrylhydrazyl radical (DPPH ) and in ferric reducing antioxidant power (FRAP).

Nothofagin is a prominent bioactive ingredient of rooibos tea. We recently reported its synthesis through a glucosyltransferase cascade reaction involving 3′-C-β-D-glucosylation of the dihydrochalcone phloretin from uridine 5′-diphosphate (UDP)-glucose and in situ formation of UDP-glucose from sucrose and catalytic amounts of UDP. Here we show that the limitation in process efficiency caused by the vanishingly low water solubility of phloretin – a major problem for biocatalytic modifications of hydrophobic natural products in general – was overcome effectively using phloretin inclusion complexation with β-cyclodextrin. Unlike operating in a two-phase system containing uncomplexed insoluble phloretin or using organic cosolvents, the addition of β-cyclodextrin inclusion complexes was well tolerated regarding enzyme activity and stability. Besides enhancing the effective phloretin concentration in water (∼0.2 mM) to about 50 mM, inclusion complexation offered the additional advantage of overcoming the complex inhibition/inactivation effect of the free/microaggregated dihydrochalcone acceptor. Thus oversaturated phloretin solution was transformed in a single batch reaction in excellent conversion (99% in solution; 88% overall) and isolated yield (78%; 17.0 g L−1). The UDP-glucose was regenerated up to ∼90 times and the nothofagin space-time yield of 2.4 mM h−1 presented an eight-fold improvement compared to a reference reaction using 20% DMSO (dimethyl sulfoxide) and requiring controlled phloretin feed. We thus demonstrate the high potential of inclusion complexation by cyclodextrins for boosting the glycosylation of hydrophobic flavonoid-like natural products.

Increasing evidence of the beneficial properties of polyphenols has led to a need for compositional data of foods and beverages to enable calculation of their dietary intake. The South African herbal tea, honeybush, produced from several Cyclopia species, has developed a global market during the past two decades. This herbal tea contributes to the dietary intake of compounds belonging to the xanthone, benzophenone, dihydrochalcone, flavanone and flavone sub-classes. The phenolic composition of C. genistoides, C. subternata, C. maculata and C. longifolia infusions at ‘cup-of-tea’ strength was determined using validated species-specific high-performance liquid chromatography with diode array detection (HPLC-DAD) methods. Major compounds present in one or more species included mangiferin, isomangiferin, vicenin-2, scolymoside, eriocitrin, hesperidin, iriflophenone-3-C-glucoside, iriflophenone-3-C-glucoside-4-O-glucoside, phloretin-3′,5′-di-C-glucoside and 3-hydroxyphloretin-3′,5′-di-C-hexoside. Phenolic content data showed large intra- and inter-species variation. Infusions of C. subternata, having the lowest levels of the xanthones, contained on average 0.3 mg mangiferin and 0.4 mg isomangiferin per 200 mL serving. Infusions of C. genistoides, having the highest levels of the xanthones, contained on average 20.4 and 7.1 mg (per serving) of mangiferin and isomangiferin, respectively. Consumption of C. genistoides infusions will also contribute the most to the dietary intake of benzophenones, with iriflophenone-3-C-glucoside-4-O-glucoside as its major benzophenone (6.4 mg per serving).

Seven dihydrochalcone compounds were isolated from the leaves of Malus crabapples, cv. "Radiant", and their chemical structures were elucidated by UV, IR, ESI-MS, ¹H-NMR and (13)C-NMR analyses. These compounds, which include trilobatin (A1), phloretin (A2), 3-hydroxyphloretin (A3), phloretin rutinoside (A4), phlorizin (A5), 6''-O-coumaroyl-4'-O-glucopyranosylphloretin (A6), and 3'''-methoxy-6''-O-feruloy-4'-O-glucopyranosyl-phloretin (A7), all belong to the phloretin class and its derivatives. Compounds A6 and A7 are two new rare dihydrochalcone compounds. The results of a MTT cancer cell growth inhibition assay demonstrated that phloretin and these derivatives showed significant positive anticancer activities against several human cancer cell lines, including the A549 human lung cancer cell line, Bel 7402 liver cancer cell line, HepG2 human ileocecal cancer cell line, and HT-29 human colon cancer cell line. A7 had significant effects on all cancer cell lines, suggesting potential applications for phloretin and its derivatives. Adding a methoxyl group to phloretin dramatically increases phloretin's anticancer activity.

In folk medicine, Stahlianthus thorelii Gagnep. has been used to treat diseases related to inflammation, ulcers, and cancer. There are no reports concerning the chemical components and bioactivities of S. thorelii, thus, this study aims to explore the phytochemicals, quantify the main compounds, and test the anticancer activity of isolates from S. thorelii. Dried rhizomes were extracted with 95% ethanol and, then, partitioned, fractionated, and isolated. On the basis of the result of the antiproliferative activity of the fractions, seven isolates were yielded and were identified by spectroscopic analyses. The inhibition of cancer proliferation was determined by an MTT assay and the deployed IC50 to value their efficacy. Seven compounds containing one new C-benzylated dihydrochalcone derivative, thorechalcone A (1) and 2&ndash, 7 were isolated from S. thorelii. In terms of the bioactivity, compounds 1 and 3 displayed promising antiproliferative activity (WiDr, A549, and HepG2), with IC50 values &lt, 40 &micro, M. The HPLC-UV method of quantification of two major compounds (3 and 4) was also validated. This study presented the isolations of antiproliferative potentials of new chalcone and known flavonoid derivatives from S. thorelii. The validated simple, accurate, and rapid HPLC method could be deployed for the quality control of herbal drugs.

Dihydrochalcone class of compounds displays good performance in taste modulation on several natural non-caloric/low-caloric sweeteners. Compounds such as hesperetin dihydrochalcone (HDC) and hesperetin dihydrochalcone-4′- O-β-d-glucoside (HDCG) were reported to be found in nature. However, the evidence was not complete to support their natural presence. The Coca-Cola Company has been working on the identification of natural sources of reported dihydrochalcones, as well as the exploration of new natural dihydrochalcones. During the investigation on plant Balanophora harlandii, the natural presence of HDCG was confirmed, and 3 new analogs have been identified. In this paper, detailed structural elucidation of known HDCG and 3 new analogs have been described.

Background and objective The Red Sea seagrass Halophila stipulacea (Forsskal) Ascherson and Thalassodendron ciliatum (Forsskal) den Hartog were poorly investigated either for their biological activities or for chemical constituents. This study aims to investigate the phytochemical constituent of both grass, along with studying the different biological activities (osteoclastogenesis, antioxidant activity, and anticancer activity) of the crude extract as well as purified compounds. Materials and methods The present study used three different in-vitro bioassay methods to screen the fractions and/or isolated compounds of both seagrass, to assess their possible biological activity. Osteoclastogenesis assay, antioxidant activity, and anticancer activity were carried out using different assays of the different anticancer mechanism of action. Results and conclusion Ten secondary metabolites were isolated and identified for the first time from Red Sea seagrass H. stipulacea (Forsskal) Ascherson: (1) p-hydroxybenzoic acid, (2) bis(2-ethyl hexyl) phthalate, (3) benzoic acid, (4) p-hydroxybenzaldehyde, (5) thymidine, (6) stigmasterol, (7) oleic acid, (8) linoleic acid, (9) linoleic methyl ester, and (10) apigenin. Furthermore, a new dihydrochalcone and a known flavonoid were isolated and identified from Red Sea seagrass T. ciliatum (Forsskal) den Hartog: (11) 2,4′ dihydroxy-4-methoxy-6-glucosyl dihydrochalcone (Thalassodendron B) and (12) rutin. Fractions of both seagrass showed promising biological activities.

The antioxidant capacity (AC) of six dihydrochalcone compounds was evaluated using DPPH and ABTS assays. In water-based solution 3-hydroxyphlorizin exhibited the highest AC among all dihydrochalcones. In acetone and acidic solutions (pH = 2.5 or 2.0), presence of an o-dihydroxyl at the B-ring increased AC, whereas glycosylation at the A-ring decreased AC of dihydrochalcones. By comparing the AC of dihydrochalcones with similar structures, it was found that the o-dihydroxyl at the B-ring and 2′-hydroxyl group at the A-ring were critical for maintaining the AC of dihydrochalcones by promoting hydrogen atom transfer or single electron transfer mechanism. Sequential proton-loss electron transfer commonly occurred during free radical scavenging in water-based solution. Moreover, we report a unique phenomenon in which glycosylation at the 2′-position enhanced the dissociation ability of the 4′-hydroxyl group and increased the AC of dihydrochalcones containing o-dihydroxyl. We speculate that this increase in AC might occur through intramolecular electron transfer.

The root bark of Ulmus davidiana var. japonica (Ulmaceae), commonly known as yugeunpi, has been used as a traditional Korean medicine for the treatment of gastroenteric and inflammatory disorders. As part of continuing projects to discover bioactive natural products from traditional medicinal plants with pharmacological potential, phytochemical investigation of the root bark of this plant was carried out. This led to the successful isolation of a new chromane derivative (1) and 22 known compounds: catechin derivatives (2–5), megastigmane glycoside (6), dihydrochalcone glycosides (7 and 8), flavanone glycosides (9 and 10), coumarins (11 and 12), lignan derivatives (13–17), and phenolic compounds (18–23). The structure of the new compound (1) was determined with 1D and 2D NMR spectroscopy and HR-ESIMS, and its absolute configurations were achieved by chemical reactions and the gauge-including atomic orbital (GIAO) NMR chemical shifts calculations. All the isolated compounds were evaluated for their potential biological activities including neuro-protective, anti-neuroinflammatory, and anti-Helicobacter pylori activities. Among the isolates, compounds 1, 8, and 20 displayed stronger potency by causing a greater increase in the production and the activity of nerve growth factor (NGF) in C6 glioma cells (147.04 ± 4.87, 206.27 ± 6.70, and 143.70 ± 0.88%, respectively), whereas compounds 11, 14, and 19 inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated murine microglial cells (IC50 of 18.72, 12.31, and, 21.40 µM, respectively). In addition, compounds 1, 11, 18, and 20 showed anti-H. pylori activity with MIC values of 25 or 50 µM against two strains of H. pylori 51 and 43504. These findings provide scientific evidence that supports the traditional usage of U. davidiana var. japonica root bark in the treatment of gastroenteric and inflammatory disorders.

A phytochemical investigation of the roots of Bupleurum chinese DC. led to the isolation of eighteen compounds, including three chromones (1–3), seven flavonoids (4–10), one dihydrochalcone (11), two phenylpropanoid glycosides (12–13), one lignan (14), three sterols (15–17) and one stilbenoid (18). Their structures were elucidated on the basis of NMR spectroscopic analysis and comparison with literature data. Compounds 6–7, 11–14 and 18 were firstly reported from the genus Bupleurum and the family Apiaceae. Moreover, the chemotaxonomic value of the isolates was also discussed.

The bioactive hydrophilic dihydrochalcone, aspalathin, has poor stability and bioavailability hampering its use in functional food ingredients with standardised aspalathin content. The aim of the study was to produce nanoparticles with controlled release to overcome these obstacles. Nanoencapsulation was investigated using both natural (chitosan and lecithin) and synthetic (poly(lactide-co-glycolide) and Eudragit S100® (ES100)) polymers by suitable conventional methods and electrospraying for all polymers. All polymer-method combinations produced particles smaller than 1.1 µm. Electrospraying produced more favourable results than conventional methods for the synthetic polymers, resulting in spherical particles with higher (p 0.05) encapsulation efficiencies (50%) and loading capacities (10%). Opposite trends were observed for natural polymers. An in vitro release study revealed biphasic aspalathin release profiles at pH 7.4 with ES100 electrosprayed nanoparticles having the slowest (p 0.05) release rate (1.67 h

The study determined the comparative antioxidant capacities of five similar dihydrochalcones: phloretin, phloridzin, trilobatin, neohesperidin dihydrochalcone, and naringin dihydrochalcone. In the ferric-reducing antioxidant power (FRAP) assay, the antioxidant activities of pairs of dihydrochalcones had the following relationship: phloretin > phloridzin, phloretin > trilobatin, trilobatin > phloridzin, trilobatin > naringin dihydrochalcone, and neohesperidin dihydrochalcone > naringin dihydrochalcone. Similar relative antioxidant levels were also obtained from 1,1-diphenyl-2-picryl-hydrazl radical (DPPH•)-scavenging, 2,2′-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) (ABTS•+)-scavenging, and superoxide radical (•O2−)-scavenging assays. Using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC−ESI−Q−TOF−MS/MS) analysis for the reaction products with DPPH•, phloretin, phloridzin, and trilobatin were found to yield both dihydrochalcone-DPPH adduct and dihydrochalcone-dihydrochalcone dimer, whereas naringin dihydrochalcone gave a naringin dihydrochalcone-DPPH adduct, and neohesperidin dihydrochalcone gave a dimer. In conclusion, the five dihydrochalcones may undergo redox-based reactions (especially electron transfer (ET) and hydrogen atom transfer (HAT)), as well as radical adduct formation, to exert their antioxidant action. Methoxylation at the ortho-OH enhances the ET and HAT potential possibly via p-π conjugation, whereas the glycosylation of the –OH group not only reduces the ET and HAT potential but also hinders the ability of radical adduct formation. The 2′,6′-di-OH moiety in dihydrochalcone possesses higher ET and HAT activities than the 2′,4′-di-OH moiety because of its resonance with the adjacent keto group.

Jason N Payne,1,2,* Vivek D Badwaik,3,* Hitesh K Waghwani,2,* Harsh V Moolani,2 Sarah Tockstein,2 David H Thompson,3 Rajalingam Dakshinamurthy1 1Department of Chemistry, Austin Peay State University, Clarksville, TN, USA; 2Department of Chemistry, Western Kentucky University, Bowling Green, KY, USA; 3Department of Chemistry, Multi-disciplinary Cancer Research Facility, Bindley Bioscience Center, West Lafayette, IN, USA *These authors contributed equally to this work Background: Phloridzin, an antidiabetic and antineoplastic agent usually found in fruit trees, is a dihydrochalcone constituent that has a clinical/pharmaceutical significance as a sodium-glucose linked transport 2 (SGLT2) inhibitor. While the aglycone metabolite of phloridzin, phloretin, displays a reduced capacity of SGLT2 inhibition, this nutraceutical displays enhanced antineoplastic activity in comparison to phloridzin.Purpose: The objective of this study was to develop gold nanoparticle (AuNP) mediated delivery of phloridzin and phloretin and explore their anticancer mechanism through conjugation of the dihydrochalcones and the AuNP cores.Methods: Phloridzin and phloretin conjugated AuNPs (Phl-AuNP and Pht-AuNP) were synthesized in single-step, rapid, biofriendly processes. The synthesized AuNPs morphology was characterized via transmission electron microscopy and ultraviolet-visible spectroscopy. The presence of phloridzin or phloretin was confirmed using scanning electron microscopy-energy dispersive x-ray spectroscopy. The percentage of organic component (phloridzin/phloretin) onto AuNPs surface was characterized using thermogravimetric analysis. Assessment of the antineoplastic potency of the dihydrochalcones conjugated AuNPs against cancerous cell lines (HeLa) was accomplished through monitoring via flow cytometry.Results: The functionalized AuNPs were synthesized via a single-step method that relied only upon the redox potential of the conjugate itself and required no toxic chemicals. The synthesized Phl-AuNPs were found to be in the size range of 15±5 nm, whereas the Pht-AuNP were found to be 8±3 nm, placing both conjugated AuNPs well within the size range necessary for successful pharmaceutical applications. These assays demonstrate a significant increase in the cancerous cell toxicities as a result of the conjugation of the drugs to AuNPs, as indicated by the 17.45-fold increase in the efficacy of Pht-AuNPs over pure phloretin, and the 4.49-fold increase in efficacy of Phl-AuNP over pure phloridzin.Conclusion: We report a simple, biofriendly process using the reducing and capping potential of the dihydrochalcones, phloridzin and phloretin, to synthesize stable AuNPs that have promising futures as potential antineoplastic agents. Keywords: gold nanoparticles, cancer, phloretin, phloridzin

HIV-1 transmembrane protein gp41 plays a crucial role by forming a stable six-helix bundle during HIV entry. Due to highly conserved sequence of gp41, the development of an effective and safe small-molecule compound targeting gp41 is a good choice. Currently, natural polyanionic ingredients with anti-HIV activities have aroused concern. Here, we first discovered that a glycosylated dihydrochalcone, trilobatin, exhibited broad anti-HIV-1 activity and low cytotoxicity in vitro. Site-directed mutagenesis analysis suggested that the hydrophobic residue (I564) located in gp41 pocket-forming site is pivotal for anti-HIV activity of trilobatin. Furthermore, trilobatin displayed synergistic anti-HIV activities combined with other antiretroviral agents. Trilobatin has a good potential to be developed as a small-molecule HIV-1 entry inhibitor for clinical combination therapy.

Aspalathin is a C-glucosyl dihydrochalcone that is abundantly present in Aspalathus linearis. This endemic South African plant, belonging to the Cape Floristic region, is normally used for production of rooibos, a herbal tea. Aspalathin was valued initially only as precursor in the formation of the characteristic red-brown colour of “fermented” rooibos, but the hype about the potential role of natural antioxidants to alleviate oxidative stress, shifted interest in aspalathin to its antioxidant properties and subsequently, its potential role to improve metabolic syndrome, a disease condition interrelated with oxidative stress. The potential use of aspalathin or aspalathin-rich rooibos extracts as a condition-specific nutraceutical is hampered by the limited supply of green rooibos (i.e., “unfermented” plant material) and low levels in “fermented” rooibos, providing incentive for its synthesis. In vitro and in vivo studies relating to the metabolic activity of aspalathin are discussed and cellular mechanisms by which aspalathin improves glucose and lipid metabolism are proposed. Other aspects covered in this review, which are relevant in view of the potential use of aspalathin as an adjunctive therapy, include its poor stability and bioavailability, as well as potential adverse herb-drug interactions, in particular interference with the metabolism of certain commonly prescribed chronic medications for hyperglycaemia and dyslipidaemia.

This study presents antimicrobial properties of Uvaria chamae roots, commonly used for the treatment of various infections in south Benin. Their constituents were extracted and then fractionated in order to isolate the active ingredients. Antimicrobial susceptibility tests were performed against several multidrug-resistant bacteria using the Mueller Hilton well agar diffusion method. Results showed that ethanol extracts were highly active against Gram-positive cocci. This activity was more extensive than that measured from conventional broad-spectrum antibiotics. Indeed, vancomycin-resistant enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) strains were all sensitive to this root extract. The aim of this study was to link the antimicrobial activity of the root to chemical structures. The ion mobility mass spectrometry analysis revealed for the first time the presence of ten chalcone and dihydrochalcone structures responsible for the antimicrobial activity of Uvaria chamae ethanol extracts. Two structures were described here for the first time in these roots. These findings confirm and justify the medical properties of these roots used as a traditional medicine.

A series of novel dihydrochalcone derivatives 2–7 were synthesized from dihydroisorcordoin 1 which was isolated from the aerial parts of Adesmia balsamica. The structures of all compounds were confirmed by 1H NMR, 13C NMR, and HRMS. Their anti-oomycete activity was evaluated in vitro against Saprolegnia parasitica and Saprolegnia diclina. Some of the newly synthesized compounds exhibited better anti-oomycete activities at low values compared with bronopol and fluconazole as positive controls. Among them, compound 7 exhibited strong activity, with minimum inhibitory concentration and minimum oomyceticidal concentration values of 75 and 100 μg/mL, respectively.

A group of flavones, isoflavones, flavanones, and chalcones was subjected to small-scale biotransformation studies with the Gram-negative Stenotrophomonas maltophilia KB2 strain in order to evaluate the capability of this strain to transform flavonoid compounds and to investigate the relationship between compound structure and transformation type. The tested strain transformed flavanones and chalcones. The main type of transformation of compounds with a flavanone moiety was central heterocyclic C ring cleavage, leading to chalcone and dihydrochalcone structures, whereas chalcones underwent reduction to dihydrochalcones and cyclisation to a benzo-γ-pyrone moiety. Substrates with a C-2-C-3 double bond (flavones and isoflavones) were not transformed by Stenotrophomonas maltophilia KB2.

Non-enzymatic browning during storage of fruit juice causes the development of brown color and off-flavors that ultimately lead to a decrease in consumer acceptability. This study investigates the role of Reactive Carbonyl Species (RCS) from the Maillard reaction on browning formation in apple juice during storage. Over a 10-week period under accelerated conditions (35 °C), a significant increase in brown color development was observed and positively correlated to the RCS concentrations. Supplementation experiments established causality between specific RCS and browning and allowed for the identification of glyoxal and methylglyoxal as key browning intermediates in apple juice. Finally, phloretin, a ubiquitous apple dihydrochalcone, was reported as an efficient browning suppressor by significantly reducing the RCS levels and inhibiting the color formation during storage.

In the present work, a comparative study of the detailed phenolic profile of fruit and juice samples from an Asturian cider apple breeding program was carried out. To achieve this, a fast, selective and sensitive UHPLC-DAD strategy was developed and validated. The proposed method allowed determining 49 polyphenols in apple samples and 41 phenolic compounds in apple juice samples in 18 min. Furthermore, six minor flavonoids have been quantified for the first time in apples: phloretin-hexosyl-hexoside, isorhamnetin-3-O-galactoside, isorhamnetin-3-O-glucoside, isorhamnetin-3-O-arabinopyranoside, isorhamnetin-3-O-arabinofuranoside and isorhamnetin-3-O-rhamnoside. The selectivity and reliability of this methodology allowed us to apply it in a successful manner to select the most interesting descendants from a progeny of ‘Meana’ × ‘Florina’ (a cider and a dessert apple, respectively) in terms of their phenolic composition. Descendants X9701-349, 119, 370, 120 and 069 could be proposed for cider production, since they exhibited a higher phenolic content than ‘Meana’ apple juice. Although flavan-3-ol, procyanidin and dihydrochalcone levels were similar to those observed in ‘Meana’ apple, flavonol levels increased slightly. Furthermore, it is worth noting that hydroxycinnamic acid concentration was up to three times higher. This fact could lead to an increase in cider astringency and color, as well as in cider aroma. Thus, this methodology is proposed to be applicable to the determination of the phenolic profile in other fruit and/or plant extracts.

The aim of this study was to produce a hydro-alcoholic safe antioxidant Malus pumila Miller cv Annurca peel extract (APE) useful as functional ingredient in an oil-in-water emulsion. Results showed that APE contains a hydroxycinnamic acid (chlorogenic acid), flavonol glycosides (quercetin derivatives) and a dihydrochalcone, phloridzin (phloretin-2-O-glucoside). The isoquercitrin (quercetin-3-O-glucoside) content was quantified in 0.3% w/w of extract. APE showed a significant and concentration-dependent free-radical scavenging activity correlated to its polyphenols content. No cytotoxic effect was observed in primary human epidermal keratinocyte adults and dermal fibroblast cell lines. The formulative approach led to produce a stable emulsion able to load a high amount of APE, up to 6.0% w/w. The homogenous distribution of APE in the emulsion was clearly demonstrated by fluorescence microscopy analysis. The emulsion resulted able to enhance the in vitro release rate of APE through synthetic membranes with respect to the raw material.

Star fruit (the fruit of Averrhoa carambola L., Oxalidaceae) is popular in tropical regions. Chemical study of the fruit yielded four new dihydrochalcone C-glycosides, carambolasides A (1), B (2), C (3), and D (4), in addition to hovertichoside C (5), isovitexin 2″-O-α- l -rhamnopyranoside (6), and carambolaflavone (7). Their structures were identified by spectroscopic and chemical methods, including electronic circular dichroism (ECD) calculation. Compounds 5–7 were reported from the fruit for the first time. Compounds 1–7 were evaluated for antioxidant activity using three assays. All of them exhibited 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical cation scavenging activity with IC50 values ranging from 7.6 to 3.9 µM, which were more potent than l -ascorbic acid (IC50 = 11.6 µM). However, they were inactive in scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and in ferric reducing antioxidant power (FRAP).

A methanol extract of everlasting flowers of Helichrysum arenarium L. Moench (Asteraceae) was found to inhibit the increase in blood glucose elevation in sucrose-loaded mice at 500 mg/kg p.o. The methanol extract also inhibited the enzymatic activity against dipeptidyl peptidase-IV (DPP-IV, IC50 = 41.2 μg/ml), but did not show intestinal α-glucosidase inhibitory activities. From the extract, three new dimeric dihydrochalcone glycosides, arenariumosides V–VII (2–4), were isolated, and the stereostructures were elucidated based on their spectroscopic properties and chemical evidence. Of the constituents, several flavonoid constituents, including 2–4, were isolated, and these isolated constituents were investigated for their DPP-IV inhibitory effects. Among them, chalconaringenin 2′-O-β-D-glucopyranoside (16, IC50 = 23.1 μM) and aureusidin 6-O-β-D-glucopyranoside (35, 24.3 μM) showed relatively strong inhibitory activities.

Alzheimer’s disease (AD) is an age-related neurodegenerative disease. Extensive in vitro and in vivo experiments have proved that the decreased activity of the cholinergic neuron is responsible for the memory and cognition deterioration. The alpha7 nicotinic acetylcholine receptor (α7-nAChR) is proposed to a drug target of AD, and compounds which acting as α7-nAChR agonists are considered as candidates in AD treatment. Chinese medicine Coptidis Rhizoma and its compounds are reported in various anti-AD effects. In this study, virtual screening, docking approaches and hydrogen bond analyses were applied to screen potential α7-nAChR agonists from Coptidis Rhizome. The 3D structure of the protein was obtained from PDB database. 87 reported compounds were included in this research and their structures were accessed by NCBI Pubchem. Docking analysis of the compounds was performed using AutoDock 4.2 and AutoDock Vina. The images of the binding modes hydrogen bonds and the hydrophobic interaction were rendered with PyMOL1.5.0.4. and LigPlot+ respectively. Finally, N-tran-feruloyltyramine, isolariciresinol, flavanone, secoisolariciresinol, (+)-lariciresinol and dihydrochalcone, exhibited the lowest docking energy of protein–ligand complex. The results indicate these 6 compounds are potential α7 nAChR agonists, and expected to be effective in AD treatment.

Artocarpus altilis (Parkinson) Fosberg has traditionally been used in Indonesia for the treatment of liver cirrhosis, hypertension, and diabetes. In many other countries, it is used for the treatment of malaria, yellow fever, and dengue fever. It has been reported that A. altilis extracts have antiatherosclerotic and cytoprotective effects, but its molecular targets in tumor cells are not yet fully understood. The A. altilis extracts and the partially purified fraction have been shown to inhibit STAT3 activity and the phosphorylation of STAT3 in a dose-dependent manner. To identify the active components, a bioassay-guided isolation of the partially purified fraction resulted in the identification of a geranyl dihydrochalcone, CG901. Its chemical structure was established on the basis of spectroscopic evidence and comparison with published data. The partially purified fraction and the isolated a geranyl dihydrochalcone, CG901, down-regulated the expression of STAT3 target genes, induced apoptosis in DU145 prostate cancer cells via caspase-3 and PARP degradation, and inhibited tumor growth in human prostate tumor (DU145) xenograft initiation model. These results suggest that A. altilis could be a good natural source and that the isolated compound will be a potential lead molecule for developing novel therapeutics against STAT3-related diseases, including cancer and inflammation. Copyright © 2015 John Wiley & Sons, Ltd.

Two new dihydrochalcones, 4-hydroxy-2,4'-dimethoxydihydrochalcone (1) and 3,4'-dihydroxy-2,4,6-trimethoxydihydrochalcone (2), and a new homoisoflavane, 7,3'-dihydroxy-8,4'-dimethoxyhomoisoflavane (3), along with 12 known compounds (4-15), were isolated from the red resin of Dracaena cochinchinensis (Chinese dragon's blood). Their structures were assigned by a variety of spectroscopic techniques. Diversity of cleavage pathways were proposed for dihydrochalcones and homoisoflavanes based on the mass spectroscopic behaviors of those identified compounds using hybrid ion trap-time of flight mass spectrometry. All the compounds were evaluated for their inhibitory effects on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages, and compound 9 exhibited mild inhibition of NO production in this assay with IC₅₀ value of 50.3 μM.

The aim of this review is to summarize the various naturally occurring chalcone compounds which have been isolated from different plants. Chalcones considered as obligate intermediated in flavonoid biosynthesis but they do not accumulate to appreciable degree in most plants. The largest number of natural chalcones has been isolated from species of the Leguminosae, Asteraceae and Moraceae families. Chalcone accumulating plants have often been used in traditional medicine and chalcones have therefore been studied and reported to possess many beneficial biological effects including anti-inflammatory, antimicrobial, antifungal, antioxidant, cytotoxic, antitumor and chemopreventive activities. Previously published reviews on this topic survey the biological activities of natural and synthetic chalcones but there are no comprehensive contributions on occurrence and biological activities of natural chalcones. The present study provides an overview of hydroxy or/and methoxy-substituted chalcones, methylated, prenylated, geranylated and other monomeric derivatives, chromeno- and furanochalcones, dimeric chalcones and dihydrochalcone derivatives focusing on their biosynthesis, natural sources and biological activities. On the basis of 608 references, this review covers the phytochemistry and biological activity of natural chalcones, describing 646 compounds have been appeared in the literature since 1975. The summary is aimed to initiate further pharmacobotanical, biotechnological and medicinal studies on the field of chalcone research. This contribution reviews some of the general aspects of naturally occurring chalcones including their chemical categories, focusing on plant sources and biological activities. The review covers the major works appeared in the literature from 1975 up to 2014, relating to 608 references and 646 compounds.

Two new dihydrochalcone enantiomers (+)-1 and (−)-1, along with eight known compounds 3–10, were obtained from Pteris ensiformis. The planar structures were determined on the basis of extensive 1D and 2DNMR and HRESIMS. The resolution of (+)-1 and (−)-1 was achieved by chiral HPLC analysis. The absolute configurations of (+)-1 and (−)-1 were established by the bulkiness rule using Rh2(O2CCF3)4-induced circular dichroism (ICD) method. Compounds (+)-1, (−)-1, 8, 9 and 10 exhibited the inhibitory assay of NO production in mouse macrophages stimulated by LPS, with IC50 values of 2.0, 2.5, 8.0, 9.5 and 5.6 μM, respectively. Otherwise, compound 10 showed moderate cytotoxic activity against HCT-116, HepG-2 and BGC-823 cell lines with IC50 values of 3.0, 10.5 and 6.3 μM, respectively.

Phloridzin (phloretin 2'-O-glucoside) is the most abundant phenolic compound in Malus species, accounting for up to 18% of the dry weight in leaves. Glycosylation of phloretin at the 2' position is the last and key step in phloridzin biosynthesis. It is catalyzed by a uridine diphosphate (UDP)-glucose:phloretin 2'-O-glucosyltransferase (P2'GT), which directly determines the concentration of phloridzin. However, this process is poorly understood. We conducted a large-scale investigation of phloridzin accumulations in leaves from 64 Malus species and cultivars. To identify the responsible P2'GT, we performed a genome-wide analysis of the expression patterns of UDP-dependent glycosyltransferase genes (UGTs). Two candidates were screened preliminarily in Malus spp. cv. Adams (North American Begonia). Results from further qRT-PCR analyses of the genotypes showed a divergence in phloridzin production. Our assays of enzyme activity also suggested that MdUGT88F4 and MdUGT88F1 regulate the conversion of phloretin to phloridzin in Malus plants. Finally, when they were silenced in 'GL-3' ('Royal Gala'), the concentrations of phloridzin and phloretin (and trilobatin) were significantly reduced and increased, respectively.

Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer) tested at 1–150 µM had an apparent rate of permeability (Papp) typical of poorly absorbed compounds (1.73 × 10−6 cm/s). Major glucose transporters, sodium glucose linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), and efflux protein (P-glycoprotein, PgP) (1.84 × 10−6 cm/s; efflux ratio: 1.1) were excluded as primary transporters, since the Papp of aspalathin was not affected by the presence of specific inhibitors. The Papp of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM), which decreased the Papp value to 2.9 × 10−7 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated) were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly.

Five dihydrochalcone compounds, including phlorizin, trilobatin, 3-hydroxyphlorizin, sieboldin and phloretin 2'-xyloglucoside, were isolated from ornamental Malus 'Red Splendor' fruit. The chemical structures of these compounds were elucidated by LC-ESI-MS and NMR. Phloretin and 3-hydroxyphloretin were produced by hydrolysis. The antioxidant capacities of these seven compounds were examined by DPPH and ABTS assays, while their cytotoxicity to five cancer cell lines were evaluated by the MTT assay. The results showed that the DPPH assay mainly reflected the antioxidant capacity of the B ring, whereas the ABTS assay was mostly related to the A ring of the dihydrochalcone molecule. Moreover, 3-hydroxyphloretin was the best antioxidant among the seven compounds. Both glycosylation of the A ring and the ortho phenolic hydroxyl groups of the B ring were important for the cytotoxicity of dihydrochalcone molecules. Sieboldin and 3-hydroxyphlorizin exhibited better cytotoxicity than other dihydrochalcone compounds. Dihydrochalcones from Malus may benefit human health.

Dihydrochalcones are a class of secondary metabolites, whose demand in biological and pharmacological applications is rapidly growing. Phloretin is one of the best known and abundant dihydrochalcone characterized by the presence of 2,6-dihydroxyacetophenone pharmacophore. It is a versatile molecule with anticancer, antiosteoclastogenic, antifungal, antiviral, anti-inflammatory, antibacterial and estrogenic activities and able to increase the fluidity of biological membranes and penetration of administered drugs. In this review we have performed a critical evaluation of available literature as far as phloretin beneficial effects and activation/block of intracellular signal cascade are of concern. In addition, we supply useful information on its chemical properties, sources and bioavailability.

A new dihydrochalcone glycoside, phloretin-4-O-β-D-glucopyranoside (1), together with seven known flavonoids (2–8), were isolated from the stems of Homalium stenophyllum. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. The known compounds (2–8) were isolated from the genus Homalium for the first time. All compounds were evaluated for their antibacterial activities against six pathogenic bacteria in vitro.

C-Glycosides are characterized by their C-C bonds in which the anomeric carbon of the sugar moieties is directly bound to the carbon atom of aglycon. C-Glycosides are remarkably stable, as their C-C bonds are resistant to glycosidase or acid hydrolysis. A variety of plant species are known to accumulate C-glycosylflavonoids; however, the genes encoding for enzymes that catalyze C-glycosylation of flavonoids have been identified only from Oryza sativa (rice) and Zea mays (maize), and have not been identified from dicot plants. In this study, we identified the C-glucosyltransferase gene from the dicot plant Fagopyrum esculentum M. (buckwheat). We purified two isozymes from buckwheat seedlings that catalyze C-glucosylation of 2-hydroxyflavanones, which are expressed specifically in the cotyledon during seed germination. Following purification we isolated the cDNA corresponding to each isozyme [FeCGTa (UGT708C1) and FeCGTb (UGT708C2)]. When expressed in Escherichia coli, both proteins demonstrated C-glucosylation activity towards 2-hydroxyflavanones, dihydrochalcone, trihydroxyacetophenones and other related compounds with chemical structures similar to 2',4',6'-trihydroxyacetophenone. Molecular phylogenetic analysis of plant glycosyltransferases shows that flavonoid C-glycosyltransferases form a different clade with other functionally analyzed plant glycosyltransferases.

A high-performance liquid chromatographic (HPLC) method coupled with diode-array detection (DAD) was optimized for the qualitative analysis of aqueous extracts of Cyclopia genistoides. Comprehensive insight into the phenolic profile of unfermented and fermented sample extracts was achieved with the identification of ten compounds based on comparison with authentic reference standards and the tentative identification of 30 additional compounds by means of electrospray ionization mass spectrometry (ESI-MS) and tandem MS detection. Three iriflophenone-di-O,C-hexoside isomers, three xanthone-dihydrochalcone derivatives and one dihydrochalcone are herein tentatively identified for the first time in C. genistoides. Of special interest is one iriflophenone-di-O,C-hexoside present in large amounts. New compounds (tentatively) identified for the first time in this species, and also in the genus Cyclopia, include two aromatic amino acids, one flavone, an iriflophenone-di-C-hexoside, a maclurin-di-O,C-hexoside, two tetrahydroxyxanthone-C-hexoside isomers, a tetrahydroxyxanthone-di-O,C-hexoside, two symmetric tetrahydroxyxanthone-C-hexoside dimers, nine glycosylated flavanone derivatives and five glycosylated phenolic acid derivatives. The presence of new compound subclasses in Cyclopia, namely aromatic amino acids and glycosylated phenolic acids, was demonstrated. The HPLC-DAD method was successfully validated and applied to the quantitative analysis of the paired sample extracts. In-depth analysis of the chemical composition of C. genistoides hot water extracts gave a better understanding of the chemistry of this species that will guide further research into its medicinal properties and potential uses.

A phytochemical investigation of an ethanolic extract from Populus balsamifera L. buds resulted in the isolation and characterization of twelve new flavan derivatives consisting of six pairs of enantiomers. Structures of (+) and (-)-balsacones D-I were elucidated based on spectroscopic data (1D and 2D NMR, MS) and their absolute configurations were established using X-ray single crystal diffraction analysis and ECD computational calculations. Antibacterial activity and cytotoxicity of all purified enantiomers were evaluated in vitro against Staphylococcus aureus and human skin fibroblast cells, respectively.

In this work, anticholinesterase activities of 24 polyphenolic compounds were tested using the modified Ellman’s spectrophotometric method. The most efficient acetyl- and butyrylcholinesterase inhibitors were anthocyanins (pelargonidin, delphinidin and cyanidin), flavones (apigenin and lu teolin), flavonols (quercetin, kaempferol and myricetin), as well as dihydrochalcone phloridzin and prenylated chalcone xanthohumol. It was estab lished that all the tested compounds were within a narrow molecular weight range of 254.24–354.40 g/mol, which probably was not discriminative for their inhibitory activity. Among all the classes of polyphenolic compounds, the lowest activities were exerted by flavan-3-ols. The inhibitory activ ity of the tested polyphenols was decreased by the presence of a 3-hydroxyl group. A simultaneous substitution of a carbonyl group at position 4 and a hydroxyl group at position 3 or a lack of both of these substitutions had no effect on the activity of the investigated compounds. The number and position of other hydroxyl groups in the tested molecules played a minor role in this context. Aglycons were more effective cholinesterase inhibitors than their corresponding glycosylated forms. Overall, the results show that phenolic acids can play a role in neuroprotection. However, further in vitro and in vivo studies involving a larger number of polyphenolic compounds simultaneously with well-known cholinesterase inhibitors should be performed in the nearest future to confirm these findings.

The formation of methylenebis(chalcone)s has been discovered during deprotection with methoxymethyl groups from trihydroxychalcones. Studies on this methylenation reaction led to a mechanism hypothesis that was extended to other chalcones and to dihydrochalcone, acetophenone, benzophenone and flavone derivatives. This new method was applied to the rapid synthesis of natural product piperanduncin C. These original methylenebis compounds were also evaluated for their antiparasitic activity.

One new dihydrochalcone diglycoside has been isolated from the EtOAc fraction of the Egyptian seagrass Thalassodendrin ciliatum (Forsk.) den Hartog, and was identified as 6′-O-rhamnosyl-(1? → 6″)-glucopyranosyl asebogenin for which a trivial name Thalassodendrone was established. Furthermore, five known phenolics were isolated and identified as asebotin, quercetin 3,7-diglucoside, protocatechuic acid, ferulic acid and p-hydroxybenzoic acid. The structures of all the isolated compounds were established based on 1D and 2D NMR spectroscopy and high-resolution-mass spectrometer. High-resolution electrospray ionization mass spectra (HR-ESI-MS) were obtained using a JEOL JMS-T100TD spectrometer (JEOL Ltd., Tokyo, Japan). The anti-influenza A virus activity of the isolated new compound and asebotin was evaluated, and the obtained results revealed that the inhibition dose concentration of asebotin was more than that of Thalassodendrone with IC 50 = 2.00 and 1.96 μg/mL, respectively, and with cytotoxic concentration (CC50) of 3.36 and 3.14 μg/mL, respectively., Natural Product Research, 28(6), pp.377-382; 2014

The antidiabetic activity test through a mechanism of inhibition of α-glucosidase enzyme was studied against ethanol, n-hexane, ethyl acetate and n-butanol fractions of ethanol extract of Artocarpus altilis (Parkinson) Fosberg (Moraceae) leaves and four flavonoid compounds isolated from ethyl acetate extracts of A. altilis. Ethyl acetate fraction has strongest antidiabetic activity compared to ethanol, n-hexane, and n-butanol fractions with IC50 values 5.98, 6.79, 440.18 and 14.42 μg/mL, respectively. Four flavonoid compounds (1-(2,4-dihydroxyphenyl)-3-[8-hydroxy2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-5-yl]-1-propanone (AC-31), 2-geranyl-2',3,4,4'-tetrahydroxy dihydrochalcone (AC-51), 8-geranyl-4',5,7-trihydroxyflavone (AC-33) and cyclocommunol (AA-3), have been isolated from ethyl acetate fraction. AC-31 was the strongest antidiabetic compound compared to AC-51, AC-33 and cyclocommunol with IC50 values are 15.73, 24.41, 49.49, and 72.20 μg/mL. Kinetic studies of AC-31 using Lineweaver-Burk method showed that inhibition mechanism of enzyme α-glucosidase was a non-competitive type.

An efficient 2'-O- to 3'-C-β-d-glucosidic bond rearrangement on the dihydrochalcone phloretin to convert phlorizin into nothofagin was achieved by combining complementary O-glycosyltransferase (OGT) and C-glycosyltransferase (CGT) activities in a one-pot transformation containing catalytic amounts of uridine 5'-diphosphate (UDP). Two separate enzymes or a single engineered dual-specific O/CGT were applied. Overall (quantitative) conversion occurred in two steps via intermediary UDP-glucose and phloretin.

Regioselective O-β-D-glucosylation of flavonoid core structures is used in plants to create diverse natural products. Their prospective application as functional food and pharmaceutical ingredients makes flavonoid glucosides interesting targets for chemical synthesis, but selective instalment of a glucosyl group requires elaborate synthetic procedures. We report glycosyltransferase-catalysed cascade reactions for single-step highly efficient O-β-D-glucosylation of two major dihydrochalcones (phloretin, davidigenin) and demonstrate their use for the preparation of phlorizin (phloretin 2′-O-β-D-glucoside) and two first-time synthesised natural products, davidioside and confusoside, obtained through selective 2′- and 4′-O-β-D-glucosylation of the dihydroxyphenyl moiety in davidigenin, respectively. Parallel biocatalytic cascades were established by coupling uridine 5′-diphosphate (UDP)-glucose dependent synthetic glucosylations catalysed by herein identified dedicated O-glycosyltransferases (OGTs) to UDP dependent conversion of sucrose by sucrose synthase (SuSy; from soybean). The SuSy reaction served not only to regenerate the UDP-glucose donor substrate for OGT (up to 9 times), but also to overcome thermodynamic restrictions on dihydrochalcone β-D-glucoside formation (up to 20% conversion and yield enhancement). Using conditions optimised for overall coupled enzyme activity, target 2′-O- or 4′-O-β-D-glucoside was obtained in ≥88% yield from reactions consisting of 5 mM dihydrochalcone acceptor, 100 mM sucrose, and 0.5 mM UDP. Davidioside and confusoside were isolated and their proposed chemical structures confirmed by NMR. OGT-SuSy cascade transformations present a green chemistry approach for efficient glucosylation in natural products synthesis.

Limited performance of one dimensional chromatographic methods provides the incentive for the development of multidimensional chromatographic techniques for the analysis of complex mixtures. Rooibos (Aspalathus linearis) represents such a complex sample, containing a range of phenolic compounds that cannot be separated and identified using a single chromatographic technique within a reasonable run time. By implementing NP high performance countercurrent chromatography (NP-HPCCC) in the first dimension (1D) and RP ultra-high pressure LC (RP-UHPLC) in the second dimension (2D), a highly orthogonal (∼80%) off-line comprehensive two-dimensional separation of rooibos phenolic compounds was achieved in a total analysis time of 17h. The use of a gradient for the 1D HPCCC separation ensured a good spread of relatively polar flavonoid di-C-glycosides and less polar mono- and di-O-glycosides, while the highly efficient UHPLC method was able to separate compounds eluting in the same 1D fraction. Analysis of green ("unfermented") and traditional "fermented" rooibos samples enabled tentative identification of 39 phenolic compounds based on UV-vis and MS characteristics, of which 18 have not previously been reported in rooibos. Scolymoside (a flavone), hesperidin (a flavanone) and phloretin-3',5'-di-C-β-d-glucopyranoside (a dihydrochalcone) were identified for the first time in rooibos by comparison with authentic reference standards.