On the Cholesterol Raising Effect of Coffee Diterpenes Cafestol and 16--Methylcafestol: Interaction with Farnesoid X Receptor.

The diterpene cafestol represents the most potent cholesterol-elevating compound known in the human diet, being responsible for more than 80% of the effect of coffee on serum lipids, with a mechanism still not fully clarified. In the present study, the interaction of cafestol and 16--methylcafestol with the stabilized ligand-binding domain (LBD) of the Farnesoid X Receptor was evaluated by fluorescence and circular dichroism. Fluorescence quenching was observed with both cafestol and 16--methylcafestol due to an interaction occurring in the close environment of the tryptophan W454 residue of the protein, as confirmed by docking and molecular dynamics.

In Vitro and In Vivo Evaluation of the Effects of Drug 2c and Derivatives on Ovarian Cancer Cells.

Background: The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting the ubiquitin-proteasome-dependent degradation of proteins.

Identification and evaluation of antiviral activity of novel compounds targeting SARS-CoV-2 virus by enzymatic and antiviral assays, and computational analysis.

The viral genome of the SARS-CoV-2 coronavirus, the aetiologic agent of COVID-19, encodes structural, non-structural, and accessory proteins. Most of these components undergo rapid genetic variations, though to a lesser extent the essential viral proteases. Consequently, the protease and/or deubiquitinase activities of the cysteine proteases M and PL became attractive targets for the design of antiviral agents.

Designing New Hybrid Antibiotics: Proline-Rich Antimicrobial Peptides Conjugated to the Aminoglycoside Tobramycin.

Resistance to aminoglycoside antibiotics is a serious problem, typically arising from inactivating enzymes, reduced uptake, or increased efflux in the important pathogens for which they are used as treatment. Conjugating aminoglycosides to proline-rich antimicrobial peptides (PrAMPs), which also target ribosomes and have a distinct bacterial uptake mechanism, might mutually benefit their individual activities. To this aim we have developed a strategy for noninvasively modifying tobramycin to link it to a Cys residue and through this covalently link it to a Cys-modified PrAMP by formation of a disulfide bond.

Novel synthesis of 1,2-diaza-1,3-dienes with potential biological activity from cinnamic acids and diazonium salts of anilines.

Cinnamic acids are an important class of phenolic compounds, which have many beneficial effects on human health but are also interesting synthetic intermediates thanks to the presence of several reactive sites. While studying the reactivity of cinnamic acids with diazonium salts from aromatic amines, an unexpected reactivity has been discovered, leading to the formation of 1,2-diaza-1,3-dienes instead of traditional diazo-coupling products. The new compounds have been fully characterized by mono and bidimensional NMR spectroscopy and mass spectrometry.

Fluorescent Imprinted Nanoparticles for Sensing of Chlorogenic Acid in Coffee Extracts.

Green coffee beans are particularly rich in chlorogenic acids (CGAs), and their identification and quantification are usually performed by HPLC, coupled with mass spectrometry (LC-MS). Although there are a few examples of molecularly imprinted polymers (MIPs) for chlorogenic acid (5-CQA) recognition present in the literature, none of them are based on optical fluorescence, which is very interesting given its great sensitivity. In the present manuscript, fluorescent polymeric imprinted nanoparticles were synthetized following the non-covalent approach using hydrogenated 5--caffeoylquinic acid (H-5-CQA) as the template.

Chitosan-Based Biocompatible Copolymers for Thermoresponsive Drug Delivery Systems: On the Development of a Standardization System.

Chitosan is a natural polysaccharide that is considered to be biocompatible, biodegradable and non-toxic. The polymer has been used in drug delivery applications for its positive charge, which allows for adhesion with and recognition of biological tissues via non-covalent interactions. In recent times, chitosan has been used for the preparation of graft copolymers with thermoresponsive polymers such as poly--vinylcaprolactam (PNVCL) and poly--isopropylamide (PNIPAM), allowing the combination of the biodegradability of the natural polymer with the ability to respond to changes in temperature.

The Pseudo-Symmetric -benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation.

Here, we report the synthesis, enzyme inhibition and structure-activity relationship studies of a new potent class of HIV-1 protease inhibitors, which contain a pseudo-symmetric hydroxyethylamine core and heteroarylcarboxyamide moieties. The simple synthetic pathway furnished nine compounds in a few steps with high yields. The compounds were designed taking into account our previous results on other series of inhibitors with different substituents at P' and P'' and different ways of linking them to the inhibitor core.

Thermoresponsive Chitosan-Grafted-Poly(-vinylcaprolactam) Microgels via Ionotropic Gelation for Oncological Applications.

Microgels can be considered soft, porous and deformable particles with an internal gel structure swollen by a solvent and an average size between 100 and 1000 nm. Due to their biocompatibility, colloidal stability, their unique dynamicity and the permeability of their architecture, they are emerging as important candidates for drug delivery systems, sensing and biocatalysis. In clinical applications, the research on responsive microgels is aimed at the development of "smart" delivery systems that undergo a critical change in conformation and size in reaction to a change in environmental conditions (temperature, magnetic fields, pH, concentration gradient).

Characterization of Thermoresponsive Poly-N-Vinylcaprolactam Polymers for Biological Applications.

Poly-N-Vinylcaprolactam (PNVCL) is a thermoresponsive polymer that exhibits lower critical solution temperature (LCST) between 25 and 50 °C. Due to its alleged biocompatibility, this polymer is becoming popular for biomedical and environmental applications. PNVCL with carboxyl terminations has been widely used for the preparation of thermoresponsive copolymers, micro- and nanogels for drug delivery and oncological therapies.

Oleocanthal Quantification Using H NMR Spectroscopy and Polyphenols HPLC Analysis of Olive Oil from the Bianchera/Belica Cultivar.

The cultivar Bianchera is an autochthonous variety from the eastern part of northern Italy, but it is also cultivated in the Slovenian and Croatian peninsula of Istria where it is named Belica (Slovenia) and Bjelica (Croatia). The properties of oleocanthal, a natural anti-inflammatory ibuprofen-like compound found in commercial monocultivar extra virgin olive oils, were determined by means of both quantitative H NMR (NMR) and HPLC analyses, where NMR was identified as a rapid and reliable method for determining the oleocanthal content. The total phenolic content (TPC) was determined by means of the Folin-Ciocalteau method and the major phenols present in the olive oils were also quantified by means of HPLC analyses.

Simultaneous Quantification of Antioxidants Paraxanthine and Caffeine in Human Saliva by Electrochemical Sensing for CYP1A2 Phenotyping.

The enzyme CYP1A2 is responsible for the metabolism of numerous antioxidants in the body, including caffeine, which is transformed into paraxanthine, its main primary metabolite. Both molecules are known for their antioxidant and pro-oxidant characteristics, and the paraxanthine-to-caffeine molar ratio is a widely accepted metric for CYP1A2 phenotyping, to optimize dose-response effects in individual patients. We developed a simple, cheap and fast electrochemical based method for the simultaneous quantification of paraxanthine and caffeine in human saliva, by differential pulse voltammetry, using an anodically pretreated glassy carbon electrode.

One Pot Synthesis of Micromolar BACE-1 Inhibitors Based on the Dihydropyrimidinone Scaffold and Their Thia and Imino Analogues.

A library of dihydropyrimidinones was synthesized via a "one-pot" three component Biginelli reaction using different aldehydes in combination with β-dicarbonyl compounds and urea. Selected 2-thiooxo and 2-imino analogs were also obtained with the Biginelli reaction from thiourea and guanidine hydrochloride, respectively. The products were screened in vitro for their β-secretase inhibitory activity.

Fluorescent Imprinted Nanoparticles for the Effective Monitoring of Irinotecan in Human Plasma.

Fluorescent, imprinted nanosized polymers for the detection of irinotecan have been synthesised using a napthalimide polymerisable derivative (2-allyl-6-[2-(aminoethyl)-amino] napthalimide) as functional monomer. The imprinted polymers contain ethylene glycol dimethacrylate (EGDMA) as a cross-linker and were prepared by high dilution radical polymerisation in dimethylsulphoxide (DMSO). The material was able to rebind irinotecan up to 18 nmol/mg with good specificity.

Biosensors and Sensing Systems for Rapid Analysis of Phenolic Compounds from Plants: A Comprehensive Review.

Phenolic compounds are secondary metabolites frequently found in plants that exhibit many different effects on human health. Because of the relevant bioactivity, their identification and quantification in agro-food matrices as well as in biological samples are a fundamental issue in the field of quality control of food and food supplements, and clinical analysis. In this review, a critical selection of sensors and biosensors for rapid and selective detection of phenolic compounds is discussed.

Signal-On Fluorescent Imprinted Nanoparticles for Sensing of Phenols in Aqueous Olive Leaves Extracts.

The activation of signals in fluorescent nanosensors upon interaction with their targets is highly desirable. To this aim, several molecularly imprinted nanogels have been synthetized for the recognition of tyrosol, hydroxytyrosol and oleuropein in aqueous extracts using the non-covalent approach. Two of them contain fluorescein derivatives as co-monomers, and their fluorescence emission is switched on upon binding of the target phenols.

Hydroxycinnamoyl Amino Acids Conjugates: A Chiral Pool to Distinguish Commercially Exploited spp.

The synthesis of five hydroxycinnamoyl amides (HCAs) was accomplished and their identification and quantification in the green coffee bean samples of , , and was performed. The HCAs -coumaroyl--tyrosine , caffeoyl--phenylalanine , caffeoyl--tyrosine , and -coumaroyl--tryptophan were characteristic of the species while caffeoyl--tryptophan was present in both and , but with higher content in . The HCAs presence was also analyzed in for the first time and none of the targeted compounds was found, indicating that this species is very similar to species.

Interaction of the Coffee Diterpenes Cafestol and 16--Methyl-Cafestol Palmitates with Serum Albumins.

The main coffee diterpenes cafestol, kahweol, and 16--methylcafestol, present in the bean lipid fraction, are mostly esterified with fatty acids. They are believed to induce dyslipidaemia and hypercholesterolemia when taken with certain types of coffee brews. The study of their binding to serum albumins could help explain their interactions with biologically active xenobiotics.

New heteroaryl carbamates: Synthesis and biological screening in vitro and in mammalian cells of wild-type and mutant HIV-protease inhibitors.

New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC values between 11 and 0.

Distribution of p-coumaroylquinic acids in commercial Coffea spp. of different geographical origin and in other wild coffee species.

Quantitative analyses of mono-p-coumaroylquinic acids (pCoQAs) and total chlorogenic acids (CGAs) in green coffee commercial lots of C. arabica, C. canephora and C.

Rational design of allosteric modulators of the aromatase enzyme: An unprecedented therapeutic strategy to fight breast cancer.

Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern.

Prediction of self-assembly of adenosine analogues in solution: a computational approach validated by isothermal titration calorimetry.

The recent discovery of the role of adenosine-analogues as neuroprotectants and cognitive enhancers has sparked interest in these molecules as new therapeutic drugs. Understanding the behavior of these molecules in solution and predicting their ability to self-assemble will accelerate new discoveries. We propose a computational approach based on density functional theory, a polarizable continuum solvation description of the aqueous environment, and an efficient search procedure to probe the potential energy surface, to determine the structure and thermodynamic stability of molecular clusters of adenosine analogues in solution, using caffeine as a model.

Aqueous extracts of walnut (Juglans regia L.) leaves: quantitative analyses of hydroxycinnamic and chlorogenic acids.

Identification of both hydroxycinnamic and chlorogenic acids present in aqueous extracts of walnut leaves (Juglans regia L.) were carried out by using, for the first time, standard compounds not commercially available for qualitative identification. In particular, in addition to caffeic, ferulic, p-coumaric and sinapic acids, cis and trans mono-caffeoylquinic, dicaffeoylquinic, mono-feruloylquinic and cis and trans mono-p-coumaroylquinic acid isomers were detected and quantified by Ultra High Pressure Liquid Chromatography and the seasonal variations of these secondary metabolites were investigated.

The binding landscape of a partially-selective isopeptidase inhibitor with potent pro-death activity, based on the bis(arylidene)cyclohexanone scaffold.

Diaryldienone derivatives with accessible β-carbons show strong anti-neoplastic properties, related to their ability to make covalent adducts with free thiols by Michael addition, and low toxicity in vivo. Accumulation of poly-ubiquitylated proteins, activation of the unfolded protein response (UPR) and induction of cell death are universal hallmarks of their activities. These compounds have been characterized as inhibitors of isopeptidases, a family of cysteine-proteases, which de-conjugate ubiquitin and ubiquitin-like proteins from their targets.

Peptide biosensors for anticancer drugs: Design in silico to work in denaturizing environment.

One of the main targets in current clinical oncology is the development of a cheap device capable of monitoring in real-time the concentration of a drug in the blood of a patient. This would allow fine-tuning the dosage according to the patient's metabolism, a key condition to reduce side effects. By using surface plasmon resonance and fluorescence spectroscopy we here show that short peptides designed in silico by a recently developed algorithm are capable of binding the anticancer drug irinotecan (CPT-11) with micromolar affinity.