Identification of Honokiol-Based Scaffold to Design Tankyrase 1/2 Inhibitors by In Silico and In Vitro Studies.

Recently, we identified magnolol bioinspired derivatives as new Tankyrase 1/2 (TNKS1/2) inhibitors by our Inverse Virtual Screening protocol. Based on these findings, in the present contribution, we enlarged our investigation of neolignans to the natural product honokiol (1) and a group of its analogues (2-8). By integrating in silico analysis and Surface Plasmon Resonance experiments, we investigated the binding of tested compounds against biological target under investigations.

Magnolol derivatives as specific and noncytotoxic inhibitors of breast cancer resistance protein (BCRP/ABCG2).

The breast cancer resistance protein (BCRP/ABCG2) transporter mediates the efflux of numerous antineoplastic drugs, playing a central role in multidrug resistance related to cancer. The absence of successful clinical trials using specific ABCG2 inhibitors reveals the urge to identify new compounds to attend this critical demand. In this work, a series of 13 magnolol derivatives was tested as ABCG2 inhibitors.

Laccase-mediated synthesis of bioactive natural products and their analogues.

Laccases are a class of multicopper oxidases that catalyse the one-electron oxidation of four equivalents of a reducing substrate, with the concomitant four-electron reduction of dioxygen to water. Typically, they catalyse many anabolic reactions, in which mostly phenolic metabolites were subjected to oxidative coupling. Alternatively, laccases catalyse the degradation or modification of biopolymers like lignin in catabolic processes.

Characterization and Interaction with Biomembrane Model of Benzo[k,l]xanthene Lignan Loaded Solid Lipid Nanoparticles.

Benzo[k,l]xanthene lignans are a group of rare natural products belonging to the class of polyphenols with promising biological activities and are studied as potential chemotherapeutic agents. The lipophilic character of a xanthene core makes these molecules difficult to be used in an aqueous medium, limiting their employment in studies for pharmaceutical applications. To overcome this problem, a drug-delivery system which is able to improve the stability and bioavailability of the compound can be used.

Synthesis and in vitro evaluation of chlorogenic acid amides as potential hypoglycemic agents and their synergistic effect with acarbose.

Type 2 Diabetes mellitus is a chronic disease considered one of the most severe global health emergencies. Chlorogenic acid (1) has been shown to delay intestinal glucose absorption by inhibiting the activity of α-glucosidase (α-Glu) and α-amylase (α-Amy). In the present work, eleven chlorogenic acid amides have been synthesized and evaluated for their antioxidant properties (as DPPH and ORAC) and inhibition activity towards the two enzymes and, with the aim to obtain dual-action antidiabetic agents.

Natural Isoflavones and Semisynthetic Derivatives as Pancreatic Lipase Inhibitors.

Obesity, now widespread all over the world, is frequently associated with some chronic diseases. Thus, there is a growing interest in the prevention and treatment of obesity. To date, the only antiobesity drug is orlistat, a natural product-derived pancreatic lipase (PL) inhibitor with some undesired side effects.

A Rare Natural Benzo[,]xanthene as a Turn-Off Fluorescent Sensor for Cu Ion.

Rapid and efficient analyses of copper ions are crucial to providing key information for Cu in living cells because of their biological importance. In this study, we reported one new turn-off fluorescent sensor for Cu with a benzo[,]xanthene core, which served as an efficient cation sensor for copper ion over a wide range of other cations (Na, K, Ag, Hg, Cd, Co, Ni, Zn, Mg, and Fe) owing to the catechol group in the aromatic core. The sensor showed selectivity for Cu over other ions; the log for Cu binding to compound had a value of 13.

Synthesis, DNA/RNA-interaction and biological activity of benzo[k,l]xanthene lignans.

Interactions of two newly synthesized and six previously reported benzoxanthene lignans (BXLs), analogues of rare natural products, with DNA/RNA, G-quadruplex and HSA were evaluated by a set of spectrophotometric methods. Presence/absence of methoxy and hydroxy groups on the benzoxanthene core and minor modifications at C-1/C-2 side pendants - presence/absence of phenyl ring and presence/absence of methoxy and hydroxy groups on phenyl ring - influenced the fluorescence changes and the binding strength to double-stranded (ds-) and G-quadruplex structures. In general, compounds without phenyl ring showed stronger fluorescence changes upon binding than phenyl-substituted BXLs.

Mass Spectrometry and H-NMR Study of (Quebracho) Tannins as a Source of Hypoglycemic and Antioxidant Principles.

The ethyl acetate extract of the commercial tannin Tan'Activ QS-SOL (from wood), employed for the production of red wine, was subjected to chromatography on Sephadex LH-20, providing nine fractions (A-1-A-9), which were estimated for total phenols content (GAE), antioxidant activity (DPPH, ORAC), and hypoglycemic activity (α-glucosidase and α-amylase inhibition). All the fractions were analyzed by means of HPLC/ESI-MS/MS and H-NMR to identify the principal active constituents. Fractions A-1 and A-3 showed the highest antioxidant activity and gallic acid (), pyrogallol (), eriodictyol (), catechin (), and taxifolin () were identified as the major constituents.

Special Issue: From Natural Polyphenols to Synthetic Bioactive Analogues.

In recent years, phenolic compounds from plant sources, commonly referred to as 'plant polyphenols', have been the subject of an impressive number of research studies, to a large extent focused on the healthy properties attributed to diet polyphenols, including antioxidant, anti-inflammatory, antineoplastic, antidiabetic, neuroprotective, and other biological activities [...

Substantial Equivalence of a Transgenic Lemon Fruit Showing Postharvest Fungal Pathogens Resistance.

The development of genetically modified (GM) crops speeds up the obtainment of novel varieties with improved agronomic characteristics. However, the risk evaluation of the use of GMs is mandatory before their release in the market. In this paper, an untargeted and comprehensive nuclear magnetic resonance-based metabolomic study was carried out on the peel and flesh of a transgenic lemon clone (E23) expressing the chit42 gene and exhibiting an increased tolerance to some pathogenic fungi and on its wild type.

Synthesis of Bisphenol Neolignans Inspired by Honokiol as Antiproliferative Agents.

Honokiol (2) is a natural bisphenol neolignan showing a variety of biological properties, including antitumor activity. Some studies pointed out 2 as a potential anticancer agent in view of its antiproliferative and pro-apoptotic activity towards tumor cells. As a further contribution to these studies, we report here the synthesis of a small library of bisphenol neolignans inspired by honokiol and the evaluation of their antiproliferative activity.

C-glucosidic ellagitannins and galloylated glucoses as potential functional food ingredients with anti-diabetic properties: a study of α-glucosidase and α-amylase inhibition.

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, which can be counteracted by inhibition of α-glucosidase and α-amylase, both involved in the carbohydrate metabolism. Fourteen C-glucosidic ellagitannins and three galloylated glucoses were studied as potential α-glucosidase and α-amylase inhibitors. Most of the compounds were found to be moderate inhibitors of α-amylase, but potent inhibitors of α-glucosidase, showing low-micromolar IC values, far lower than that of the antidiabetic drug acarbose.

Novel benzoxanthene lignans that favorably modulate lipid mediator biosynthesis: A promising pharmacological strategy for anti-inflammatory therapy.

Lipid mediators (LM) encompass pro-inflammatory prostaglandins (PG) and leukotrienes (LT) but also specialized pro-resolving mediators (SPM) which display pivotal bioactivities in health and disease. Pharmacological intervention with inflammatory disorders such as osteoarthritis and rheumatoid arthritis commonly employs anti-inflammatory drugs that can suppress PG and LT formation, which however, possess limited effectiveness and side effects. Here, we report on the discovery and characterization of the two novel benzoxanthene lignans 1 and 2 that modulate select LM biosynthetic enzymes enabling the switch from pro-inflammatory LT to SPM biosynthesis as potential pharmacological strategy to intervene with inflammation.

Chemical Proteomics-Guided Identification of a Novel Biological Target of the Bioactive Neolignan Magnolol.

Understanding the recognition process between bioactive natural products and their specific cellular receptors is of key importance in the drug discovery process. In this outline, some potential targets of Magnolol, a natural bioactive compound, have been identified by proteomic approaches. Among them, Importin-β1 has been considered as the most relevant one.

Synthesis of Rosmarinic Acid Amides as Antioxidative and Hypoglycemic Agents.

Type 2 diabetes mellitus (T2DM) is an important metabolic disorder for which there is an urgent need for new antidiabetic drugs. α-Glucosidase inhibition is an established protocol for T2DM therapy. Because hyperglycemia causes oxidative tissue damage, the development of agents with both α-glucosidase inhibition and antioxidant activity from natural or natural-derived polyphenols such derivatives of rosmarinic acid (RA) represents an attractive therapeutic option.

Bioinspired benzoxanthene lignans as a new class of antimycotic agents: synthesis and spp. growth inhibition.

In this work we synthetized the bioinspired benzoxanthene lignans (BXLs) , , and the phenazine derivative as potential antimycotic agents. MICs and MFCs against strains were determined. In a preliminary screening, compounds , , , , were substantially inactive.

A mass spectrometry and H NMR study of hypoglycemic and antioxidant principles from a Castanea sativa tannin employed in oenology.

The ethanol extract of the commercial tannin Tan'Activ C, (from Castanea sativa wood), employed in oenology, was subjected to chromatography on XAD-16 affording fractions X1-X5, evaluated for total phenols content (GAE), antioxidant activity (DPPH, ORAC), and hypoglycemic activity (α-glucosidase inhibition). Fraction X3 showed GAE, radical scavenging activity, and α-glucosidase inhibition higher than those of the Castanea sativa extract, and was subjected to chromatography on Sephadex LH-20 to obtain fractions S1-S7, analyzed by HPLC/ESI-MS/MS and H NMR to identify the main active constituents. In fractions with higher antioxidant activity, gallic acid (4), grandinin (5), valoneic acid dilactone (9), 1,2,3-tri-O-galloyl-β-glucose (14), 3,4,6-tri-O-galloyl-β-glucose (15) and galloyl derivative of valoneic acid dilactone (21) were identified as the major constituents.

Identification by Inverse Virtual Screening of magnolol-based scaffold as new tankyrase-2 inhibitors.

The natural product magnolol (1) and a selection of its bioinspired derivatives 2-5, were investigated by Inverse Virtual Screening in order to identify putative biological targets from a panel of 308 proteins involved in cancer processes. By this in silico analysis we selected tankyrase-2 (TNKS2), casein kinase 2 (CK2) and bromodomain 9 (Brd9) as potential targets for experimental evaluations. The Surface Plasmon Resonance assay revealed that 3-5 present a good affinity for tankyrase-2, and, in particular, 3 showed an antiproliferative activity on A549 cells higher than the well-known tankyrase-2 inhibitor XAV939 used as reference compound.

Biological effects of polyphenol-rich extract and fractions from an oenological oak-derived tannin on in vitro swine sperm capacitation and fertilizing ability.

Although excessive ROS levels induce sperm damage, sperm capacitation is an oxidative event that requires low amounts of ROS. As the antioxidant activity of the ethanol extract (TRE) of a commercial oenological tannin (Quercus robur toasted oak wood, Tan'Activ R) and its four fractions (FA, FB, FC, FD) has been recently reported, the present study was set up to investigate the biological effects of TRE and its fractions in an in vitro model of sperm capacitation and fertilization. Boar sperm capacitation or gamete coincubation were performed in presence of TRE or its fractions (0, 1, 10, 100 μg/ml).

Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor.

Prostate cancer growth and progression are mainly dependent on androgens and many current prostate cancer treatment options target the synthesis or function of androgens. We have previously reported that resveratrol and synthetic analogs of resveratrol with a higher bioavailability inhibit the synthesis of androgens in human adrenocortical H295R cells. Now we have studied the antiandrogenic properties of resveratrol, piceatannol and analogs in two different prostate cell lines; LNCaP and RWPE.

Chain-breaking antioxidant activity of hydroxylated and methoxylated magnolol derivatives: the role of H-bonds.

Chemical modification of magnolol, an uncommon dimeric neolignan contained in Magnolia genus trees, provides a unique array of polyphenols having interesting biological activity potentially related to radical scavenging. The chain-breaking antioxidant activity of four new hydroxylated and methoxylated magnolol derivatives was explored by experimental and computational methods. The measurement of the rate constant of the reaction with ROO˙ radicals (k) in an apolar solvent showed that the introduction of hydroxyl groups ortho to the phenolic OH in magnolol increased the k value, being 2.

Chemoenzymatic Synthesis and α-Glucosidase Inhibitory Activity of Dimeric Neolignans Inspired by Magnolol.

A chemoenzymatic synthesis of a small library of dimeric neolignans inspired by magnolol (1) is reported. The 2-iodoxybenzoic acid (IBX)-mediated regioselective ortho-hydroxylation of magnolol is described, affording the bisphenols 6 and 7. Further magnolol analogues (12, 13, 15-17, 19-23) were obtained from eugenol (3), tyrosol (4), and homovanillic alcohol (5), through horseradish peroxidase (HRP)-mediated oxidative coupling and regioselective ortho-hydroxylation or ortho-demethylation in the presence of IBX, followed by reductive treatment with NaSO.

Proteasome as a New Target for Bio-Inspired Benzo[k,l]xanthene Lignans.

Mass spectrometry-based chemical proteomics is a powerful tool for the target discovery of small molecules. Here, the application of this approach is presented to define the target profile of bio-inspired synthetic benzo[k,l]xanthene lignans endowed with interesting biological properties. Proteasome has been identified as a new main interactor for this class of compounds.

α-Glucosidase inhibition and antioxidant activity of an oenological commercial tannin. Extraction, fractionation and analysis by HPLC/ESI-MS/MS and (1)H NMR.

Two batches of the oenological tannin Tan'Activ R, (toasted oak wood - Quercus robur), were extracted with ethanol. A fractionation on XAD-16 afforded four fractions for each extract. Extracts and fractions were evaluated for antioxidant activity (DPPH), polyphenol content (GAE) and yeast α-glucosidase inhibitory activity.