1-1-diphenyl-2-picrylhydrazyl and caffeic-acid-phenethyl-ester

Inhibitors of the enzyme xanthine oxidase (XO) with radical scavenging properties hold promise as novel agents against reperfusion injuries after ischemic events. By suppressing the formation of damaging reactive oxygen species (ROS) by XO or scavenging ROS from other sources, these compounds may prevent a buildup of ROS in the aftermath of a heart attack or stroke. To combine these two properties in a single molecule, we synthesized and characterized the non-purine XO inhibitor caffeic acid phenethylester (CAPE) and 19 derivatives using a convenient microwave-assisted Knoevenagel condensation protocol. Varying systematically the number and positions of the hydroxyl groups at the two phenyl rings, we derived structure-activity relationships based on experimentally determined XO inhibition data. Molecular docking suggested that critical enzyme/inhibitor interactions involved π-π interactions between the phenolic inhibitor ring and Tyr914, hydrogen bonds between inhibitor hydroxyl groups and Glu802, and hydrophobic interactions between the CAPE phenyl ring and non-polar residues located at the entrance of the binding site. To effectively scavenge the stable radical DPPH, two hydroxyl groups in 1,2- or 1,4-position at the phenyl ring were required. Among all compounds tested, E-phenyl 3-(3,4-dihydroxyphenyl)acrylate, a CAPE analog without the ethyl tether, showed the most promising properties.

Topics: Animals; Biphenyl Compounds; Caffeic Acids; Cattle; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Models, Molecular; Molecular Structure; Phenylethyl Alcohol; Picrates; Reactive Oxygen Species; Structure-Activity Relationship; Xanthine Oxidase

Caffeic acid phenethyl ester (CAPE) possesses a set of valuable biological properties: antioxidant, antibacterial, antitumor, anti-inflammatory, antiviral, etc. However, CAPE is poorly soluble in aqueous environment which is limiting its possible therapeutic applications. In the present study novel fibrous materials enhancing CAPE solubility and accelerating CAPE release were developed. The materials were prepared from poly(3-hydroxybutyrate) (PHB) by electrospinning and by electrospinning combined with dip-coating. The effects of the composition - without/with addition of polyvinylpyrrolidone (PVP) and of the design of fiber (CAPE in the bulk of the fiber or incorporated in the PVP coating) on some of the properties of these materials were studied. X-ray diffraction and differential scanning calorimetry analyses revealed that CAPE was in the amorphous state in CAPE-loaded fibers and in the PVP coating. The new CAPE-containing materials exhibited good antioxidant activity. The microbiological screening demonstrated that incorporation of CAPE in the fibers or in the coating induced complete killing of Gram-positive S. aureus and led to inhibition of the growth of Gram-negative E. coli by the fibrous materials. Moreover, pathogenic S. aureus did not adhere onto CAPE-containing fibrous mats. Therefore, the obtained materials are promising candidates for use as wound dressing materials.

Topics: Anti-Bacterial Agents; Antioxidants; Biphenyl Compounds; Caffeic Acids; Calorimetry, Differential Scanning; Crystallography, X-Ray; Dosage Forms; Drug Compounding; Escherichia coli; Hydroxybutyrates; Microscopy, Electron, Scanning; Phenylethyl Alcohol; Picrates; Polyesters; Povidone; Solubility; Spectroscopy, Fourier Transform Infrared; Staphylococcus aureus; Technology, Pharmaceutical

Breast cancer is the second leading cause of death amongst women worldwide. As a result, many have turned their attention to new alternative approaches to treat this disease. Caffeic acid phenylethyl ester (CAPE), a well-known active compound from bee propolis, has been previously identified as a strong antioxidant, anti-inflammatory, antiviral and anticancer molecule. In fact, CAPE is well documented as inducing cell death by inhibiting NFκB and by inducing pro-apoptotic pathways (i.e., p53). With the objective of developing stronger anticancer compounds, we studied 18 recently described CAPE derivatives for their ability to induce apoptosis in breast cancer cell lines. Five of the said compounds, including CAPE, were selected and subsequently characterised for their anticancer mechanism of action. We validated that CAPE is a potent inducer of caspase-dependent apoptosis. Interestingly, some newly synthesized CAPE derivatives also showed greater cell death activity than the lead CAPE structure. Similarly to CAPE, analog compounds elicited p53 activation. Interestingly, one compound in particular, analog 10, induced apoptosis in a p53-mutated cell line. These results suggest that our new CAPE analog compounds may display the capacity to induce breast cancer apoptosis in a p53-dependent and/or independent manner. These CAPE analogs could thus provide new therapeutic approaches for patients with varying genotypic signatures (such as p53 mutations) in a more specific and targeted fashion.

Topics: Apoptosis; Biphenyl Compounds; Caffeic Acids; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Female; Free Radicals; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Inhibitory Concentration 50; Luciferases; MCF-7 Cells; Mutation; Phenylethyl Alcohol; Picrates; Signal Transduction; Structure-Activity Relationship; Tumor Suppressor Protein p53

Combinations of antioxidants are believed to be more effective than single antioxidant because when antioxidants are combined they support each other synergistically to create a magnified effect. Discovering the enhancer effects or synergies between bioactive components is valuable for resisting oxidative stress and improving health benefits. The aim of this study was to investigate a possible cooperation of natural antioxidant caffeic acid phenethyl ester (CAPE) with synthetic antioxidant Trolox in the model systems of chemical generation of free radicals, lipid peroxidation of microsomes and radiation-induced oxidative injury in L929 cells. Based on the intermolecular interaction between CAPE and Trolox, the present study shows a synergistic effect of CAPE and Trolox in combination on elimination of three different free radicals and inhibition of lipid peroxidation initiated by three different systems. CAPE and Trolox added simultaneously to the L929 cells exerted an enhanced preventive effect on the oxidative injury induced by radiation through decreasing ROS generation, protecting plasma membrane and increasing the ratios of reduced glutathione/oxidized glutathione and the expression of key antioxidant enzymes mediated by nuclear factor erythroid 2 p45-related factor 2 (Nrf2). Our results showed for the first time that administration of CAPE and Trolox in combination may exert synergistic antioxidant effects, and further indicate that CAPE and Trolox combination functions mainly through scavenging ROS directly, inhibiting lipid peroxidation and promoting redox cycle of GSH mediated by Nrf2-regulated glutathione peroxidase and glutathione reductase expression.

Topics: Animals; Antioxidants; Biphenyl Compounds; Caffeic Acids; Cell Line; Cell Survival; Chromans; Free Radical Scavengers; Gamma Rays; Glutathione Disulfide; Lipid Peroxidation; Male; Mice; Microsomes, Liver; Oxidative Stress; Phenylethyl Alcohol; Picrates; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Spectrophotometry, Ultraviolet; Thiobarbituric Acid Reactive Substances

Propolis, a natural product produced by the honeybee, has been used for thousands of years in folk medicine for several purposes. The extract contains amino acids, phenolic acids, phenolic acid esters, flavonoids, cinnamic acid, terpenes and caffeic acid. It possesses several biological activities such as antiinflammatory, immunostimulatory, antiviral and antibacterial. The exact mode of physiological or biochemical mechanisms responsible for the medical effects, however, is yet to be determined. In this work, we have investigated the antioxidant activity of a propolis extract deprived of caffeic acid phenethyl ester (CAPE). In addition, the activity of CAPE and galangin was also examined. Propolis extract (with and without CAPE) and its active components showed a dose-dependent free radical scavenging effect, a significant inhibition of xanthine oxidase activity, and an antilipoperoxidative capacity. Propolis extract with CAPE was more active than propolis extract without CAPE. CAPE, used alone, exhibited a strong antioxidant activity, higher than galangin. The experimental evidence, therefore, suggests that CAPE plays an important role in the antioxidant activity of propolis.

Topics: Antioxidants; Biphenyl Compounds; Caffeic Acids; Dose-Response Relationship, Drug; Flavonoids; Free Radical Scavengers; Humans; Lipid Peroxidation; Phenylethyl Alcohol; Phytotherapy; Picrates; Plant Extracts; Propolis; Xanthine Oxidase

Two new flavonoids, 3-O-[(S)-2-methylbutyroyl]pinobanksin (1) and 6-cinnamylchrysin (2), were isolated from the EtOAc-soluble fraction of the MeOH extract of Chinese propolis, along with 12 known compounds (3-14). The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses. The isolated compounds were tested for their antiproliferative activity toward five different cancer cell lines. Benzyl caffeate (13) and phenethyl caffeate (14) showed potent antiproliferative activity toward tested cell lines with a selective activity toward colon 26-L5 carcinoma cell line (EC(50) values: 13, 1.01; 14, 0.30 microM).

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Caffeic Acids; China; Chromatography, Thin Layer; Colonic Neoplasms; Drug Screening Assays, Antitumor; Flavonoids; Free Radical Scavengers; Mice; Molecular Structure; Phenylethyl Alcohol; Picrates; Propolis; Spectrophotometry, Infrared; Tumor Cells, Cultured