benzyl-caffeate and caffeic-acid-phenethyl-ester

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

Transthyretin (TTR) is a homotetrameric serum protein associated with amyloidoses such as familial amyloid polyneuropathy and senile systemic amyloidosis. The amyloid fibril formation of TTR can be inhibited through stabilization of the TTR tetramer by the binding of small molecules. In this study, we examined the inhibitory potency of caffeic acid phenethyl ester (CAPE) and its derivatives. Thioflavin T assay showed that CAPE suppressed the amyloid fibril formation of TTR. Comparative analysis of the inhibitory potencies revealed that phenethyl ferulate was the most potent among the CAPE derivatives. The binding of phenethyl ferulate and the selected compounds to TTR were confirmed by the 8-anilino-1-naphthalenesulfonic acid displacement and X-ray crystallography. It was also demonstrated that Bio 30, which is a CAPE-rich commercially available New Zealand propolis, inhibited TTR amyloidogenesis and stabilized the TTR tetramer. These results suggested that a propolis may be efficient for preventing TTR amyloidosis.

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Caffeic Acids; Coumaric Acids; Masoprocol; Phenylethyl Alcohol; Prealbumin; Propolis

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

Efficient replication of HIV-1 requires integration of a DNA copy of the viral genome into a chromosome of the host cell. Integration is catalyzed by the viral integrase, and we have previously reported that phenolic moieties in compounds such as flavones, caffeic acid phenethyl ester (CAPE, 2), and curcumin confer inhibitory activity against HIV-1 integrase. We now extend these findings by performing a comprehensive structure-activity relationship using CAPE analogues. Approximately 30 compounds have been prepared as HIV integrase inhibitors based on the structural lead provided by CAPE, which has previously been shown to exhibit an IC50 value of 7 microM in our integration assay. These analogues were designed to examine specific features of the parent CAPE structure which may be important for activity. Among the features examined for their effects on inhibitory potency were ring substitution, side chain length and composition, and phenyl ring conformational orientation. In an assay which measured the combined effect of two sequential steps, dinucleotide cleavage and strand transfer, several analogues have IC50 values for 3'-processing and strand transfer lower than those of CAPE. Inhibition of strand transfer was assayed using both blunt-ended and "precleaved" DNA substrates. Disintegration using an integrase mutant lacking the N-terminal zinc finger and C-terminal DNA-binding domains was also inhibited by these analogues, suggesting that the binding site for these compounds resides in the central catalytic core. Several CAPE analogues were also tested for selective activity against transformed cells. Taken together, these results suggest that the development of novel antiviral agents for the treatment of acquired immune deficiency syndrome can be based upon inhibition of HIV-1 integrase.

Topics: Animals; Antiviral Agents; Apoptosis; Base Sequence; Binding Sites; Caffeic Acids; Cell Line, Transformed; DNA; DNA Nucleotidyltransferases; Enzyme Inhibitors; HIV; Humans; Hydroxylation; Integrases; Magnetic Resonance Spectroscopy; Molecular Conformation; Molecular Sequence Data; Molecular Structure; Phenylethyl Alcohol; Rats; Structure-Activity Relationship; Tumor Cells, Cultured; Zinc Fingers