Gas-phase IR cross-sections and single crystal structures data for atmospheric relevant nitrocatechols.

The gas-phase IR absorption cross sections for 3-nitrocatechol, 5-methyl-3-nitrocatechol, 4-nitrocatechol and 4-methyl-5-nitrocatechol were evaluated using the ESC-Q-UAIC (the environmental simulation chamber made of quartz from the "Alexandru Ioan Cuza" University of Iasi, Romania) photoreactor facilities. Specific infrared absorptions and integrated band intensities in the range of 650-4000 cm-1 were investigated by long path gas-phase FT-IR technique. Two different addition methods (solid and liquid transfer methods) of nitrocatechols into the reactor were employed in these investigations. All investigated nitrocatechols were synthesized and characterized by X-ray diffraction spectroscopy techniques beside traditional nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy in order to evaluate their structure-properties relationship in gas and solid phase. This study reports for the first time the gas-phase infrared cross sections and the X-ray diffraction analysis for (methyl) nitrocatechols.

Repurposing nitrocatechols: 5-Nitro-α-cyanocarboxamide derivatives of caffeic acid and caffeic acid phenethyl ester effectively inhibit aggregation of tau-derived hexapeptide AcPHF6.

Polyphenols like caffeic acid and its phenethyl ester have been associated with potent anti-aggregating activity. Accordingly, we screened a library of polyphenols and synthetic derivatives thereof for their capacity to inhibit tau-aggregation using a thioflavin T-based fluorescence method. Our results show that the nitrocatechol scaffold is required for a significant anti-aggregating activity, which is enhanced by introducing bulky substituents at the side chain. A remarkable increase in activity was observed for α-cyanocarboxamide derivatives 26-27. Molecular docking studies showed that the amide bond provides superior conformational stability in the steric zipper assembly of tau, which drives the increase in activity. We also found that derivatives 24-27 were potent chelators of copper(II) - a property of pharmacological significance in abnormal protein aggregation. These small molecules can provide promising leads to develop new drugs for tauopathies and AD. These findings open a new window on the repurposing of nitrocatechols beyond their established role as catechol-O-methyltransferase inhibitors.

Enhancing the Cancer Cell Growth Inhibitory Effects of Table Grape Anthocyanins.

The risk for breast and colon cancer may be lowered in part by high intake of fruits and vegetables. Fruits such as grapes are abundant in bioactive compounds such as anthocyanins. The potential anticancer activity of anthocyanins may be limited by their metabolism in the gut and liver. One metabolic transformation is due to the enzyme catechol-O-methyltransferase (COMT), which methylates polyphenols such as anthocyanins. Entacapone is a clinically used inhibitor of COMT, and has been shown to modulate the methylation of food-derived polyphenols. In this study, we compared the effect of entacapone on the cell viability of colon (Caco-2 and HT-29) and breast (MDA-MB-231) cancer cell lines treated with anthocyanins. Cells were treated with either cyanidin-3-glucoside, delphinidin-3-glucoside, or an anthocyanin-rich grape extract, in the absence or presence of entacapone. Cell viability was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay. Entacapone in combination with the anthocyanins had a greater than additive effect on growth inhibition of the Caco-2 cells. In the MDA-MB-231 cell line, entacapone similarly enhanced the growth inhibitory activity of the anthocyanin extract. Entacapone also had antiproliferative effects when used as a single treatment. Total hydroperoxides was quantified in the cell culture media. Greater concentrations of the treatments resulted in higher levels of total hydroperoxides, indicating that oxidative stress may be an important mechanism for growth inhibition. In conclusion, the antiproliferative activity of fruit-derived anthocyanins was improved in human cancer cell lines by the clinically used drug entacapone. The efficacy and mechanisms of entacapone/anthocyanin combinations should be carefully studied in vivo. PRACTICAL APPLICATION: Chemical components of grapes are good for our health and have been shown to lower risk for certain cancers. Their beneficial health effects could also be enhanced by consuming other molecules that improve their bioavailability.

Evaluation of the Bioavailability and Metabolism of Nitroderivatives of Hydroxytyrosol Using Caco-2 and HepG2 Human Cell Models.

Considering that nitrocatechols present putative effects against Parkinson's disease, the absorption and metabolism of nitroderivatives of hydroxytyrosol (HT) were assessed using human cell model systems. The test compounds nitrohydroxytyrosol (NO2HT), nitrohydroxytyrosyl acetate (NO2HT-A), and ethyl nitrohydroxytyrosyl ether (NO2HT-E) were efficiently transferred across human Caco-2 cell monolayers as an intestinal barrier model, NO2HT-A and NO2HT-E being better (p < 0.05) absorbed (absorption rate (AR) = 1.4 ± 0.1 and 1.5 ± 0.2, respectively) than their precursor, NO2HT (AR = 1.1 ± 0.1). A significant amount of the absorbed compounds remained unconjugated (81, 70, and 33% for NO2HT, NO2HT-A, and NO2HT-E, respectively) after incubation in Caco-2 cells, being available for hepatic metabolism. Nitrocatechols were extensively taken up and metabolized by human hepatoma HepG2 cells as a model of the human liver. Both studies revealed extensive hydrolysis of NO2HT-A into NO2HT, whereas NO2HT-E was not hydrolyzed. Glucuronide (75-55%), methylglucuronide (25-33%), and methyl derivatives (0-12%) were the main nitrocatechol metabolites detected after metabolism in Caco-2 and HepG2 cells. In conclusion, NO2HT, NO2HT-A, and NO2HT-E show high in vitro bioavailability and are extensively metabolized by hepatic cells.

Effect of intracerebral hydroxytyrosol and its nitroderivatives on striatal dopamine metabolism: A study by in vivo microdialysis.

AIMS: The natural phenolic oil compound hydroxytyrosol (HTy) is widely studied because of its antioxidant and neuroprotective properties. Nitroderivatives of HTy have been studied in order to evaluate their putative effects on catechol-O-methyltransferase (COMT) activity. MAIN METHODS: To study its effect on dopamine metabolism, nitrohydroxytyrosol and its lipophilic derivatives (nitrohydroxytyrosyl acetate and ethyl nitrohydroxytyrosyl ether), were administered into the rat corpus striatum through a microdialysis probe. Other catechols (HTy and the known COMT inhibitor Ro 41-0960) were also studied for comparison. KEY FINDINGS: The olive oil phenolic compounds (nitroderivatives and HTy) increased extracellular levels of 3,4-dihydroxyphenylacetic acid during the perfusion with similar maximum values to that of Ro 41-0960 when comparing to basal dialysate levels (approximately 140%). None of the compound series produced a decrease in the homovanillic acid extracellular levels below 75%. Among all novel compounds studied, both lipophilic nitrocatechols (nitrohydroxytyrosyl acetate and ethyl nitrohydroxytyrosyl ether) showed a long-acting effect over time once the perfusion through the microdialysis probe ended. SIGNIFICANCE: In accordance with the actual design of novel COMT inhibitors with a long profile, our results suggest a certain influence of the side chain substituent on the COMT activity that could provide new lipophilic COMT inhibitors.