ks370g and caffeic-acid-phenethyl-ester

Topics: Angiogenesis Inhibitors; Apoptosis; Caffeic Acids; Cell Line, Tumor; Down-Regulation; Genes, myc; Humans; Ikaros Transcription Factor; Interferon Regulatory Factors; Lenalidomide; Multiple Myeloma; Phenylethyl Alcohol; Sp1 Transcription Factor; Structure-Activity Relationship

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.

Topics: Caffeic Acids; Catechols; Chelating Agents; Copper; Drug Design; Nitro Compounds; Peptides; Phenylethyl Alcohol; Polyphenols; Protein Aggregation, Pathological; Small Molecule Libraries; tau Proteins; Tauopathies

A validated LCMS method was developed for the quantitative determination of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) from rat plasma. Separation was achieved using a reverse-phase C12 HPLC column (150 × 2.00 mm, 4 µm) with gradient elution running water (A) and acetonitrile (B). Mass spectrometry was performed with electrospray ionization in negative mode. This method was used to determine the pharmacokinetic profiles of CAPA and CAPE in male Sprague-Dawley rats following intravenous bolus administration of 5, 10 and 20 mg/kg of CAPA and 20 mg/kg of CAPE. The pharmacokinetic analysis suggests the lack of dose proportionality in the dose range of 5-20 mg/kg of CAPA. Total clearance values for CAPA ranged from 45 to 156 mL/min and decreased with increasing dose of CAPA. The volume of distribution for CAPA ranged from 17,750 to 52,420 mL, decreasing with increasing dose. The elimination half-life for CAPA ranged from 243.1 to 295.8 min and no statistically significant differences were observed between dose groups in the range of 5-20 mg/kg (p > 0.05). The elimination half-life for CAPE was found to be 92.26 min.

Topics: Animals; Caffeic Acids; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Limit of Detection; Linear Models; Male; Phenylethyl Alcohol; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization

A series of catechol ring-fluorinated derivatives of caffeic acid phenethyl amide (CAPA) were synthesized and screened for cytoprotective activity against H2O2 induced oxidative stress in human umbilical vein endothelial cells (HUVEC). CAPA and three fluorinated analogs were found to be significantly cytoprotective when compared to control, with no significant difference in cytoprotection between caffeic acid phenethyl ester (CAPE) and CAPA.

Topics: Caffeic Acids; Cell Line; Cytoprotection; Halogenation; Humans; Hydrogen Peroxide; Oxidative Stress; Phenethylamines; Phenylethyl Alcohol; Umbilical Veins