Prolyl endopeptidase inhibitory activity of unsaturated fatty acids.

Prolyl endopeptidase (PEP, EC 3.4.21.26) is widely distributed in various organs, particularly in the brains of amnestic patients. Evaluation of PEP levels in postmortem brains of Alzheimer's disease patients revealed significant increases in PEP activity, suggesting that a specific PEP inhibitor can be a good candidate for an antiamnestic drug. In this study, mono- and polyunsaturated fatty acids were investigated to determine their role as PEP inhibitors. Oleic, linoleic, and arachidonic acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) showed PEP inhibitory activities (IC50 values of 23.6 +/- 0.4, 43.8 +/- 1.8, 53.4 +/- 1.2, 99.4 +/- 1.2, and 46.2 +/- 1.0 microM, respectively), indicating that they were effective PEP inhibitors, with inhibition constant (Ki) values of 26.7 +/- 0.3, 51.0 +/- 0.7, 91.3 +/- 3.1, 247.5 +/- 2.6, and 89.0 +/- 2.3 microM, respectively. Oleic acid showed the highest PEP inhibitory activity. Dixon plots of PEP inhibition showed oleic, linoleic, and arachidonic acids, EPA, and DHA are noncompetitive inhibitors; despite higher IC50 values of these unsaturated fatty acids than strong natural inhibitors, they may have potential use in preventing memory loss.

Novel 1beta-methylcarbapenems with isoxazoloethenyl moieties containing carboxylic acid sodium salt.

The synthesis of novel 1beta-methylcarbapenems 1a,b having sodium 5-(3- and 5-carboxylic acid)isoxazoloethenyl moieties at C-5 position of pyrrolidine ring and their biological evaluation are described. Both compounds showed potent and well-balanced antibacterial activity as well as high stability to DHP-I. The selected sodium 3-carboxylic acid derivative 1a possessed excellent DHP-I stability and advanced pharmacokinetic parameters in comparison with 2 and meropenem.

Prolyl endopeptidase inhibitors from the leaves of Ginkgo biloba.

Prolyl endopeptidase (PEP, EC 3.4.21.26) hydrolyzes proline-containing neuropeptides, such as vasopressin, substance P, and thyrotropin-releasing hormone (TRH), and is suggested to participate in learning and memory processes. Ginkgo biloba leaves, upon examination for anti-amnestic constituents as new types of PEP inhibitors, showed significant PEP inhibition. PEP activity-guided fractionation and column chromatography of the MeOH extracts of G. biloba leaves resulted in the isolation of 6-(8'Z-pentadecenyl)salicylic acid (1) and 6-(10'Z-heptadecenyl)salicylic acid (2). The kinetic study indicated that compounds 1 and 2 are non-competitive inhibitors of prolyl endopeptidase with Ki values of 0.87 and 0.80 microM, respectively.

Isolation and characterization of water-soluble intermediates of blue pigments transformed from geniposide of Gardenia jasminoides.

Gardenia blue dye was obtained through the reaction of methylamine with genipin, the aglycone of geniposide isolated from the fruits of Gardenia jasminoides. The resulting blue pigments were passed through Bio-Gel P-2 resin yielding five fractions, GM1-GM5. Four fractions (GM1-GM4) were all blue pigments, and the first eluted higher molecular weight fraction GM1 had a higher tinctorial strength than the later eluted lower molecular weight fractions, GM2-GM4. The last eluted GM5 fraction with lambda(max) of 292 nm was colorless and was confirmed as the true intermediate of the blue pigments on the basis of UV-vis spectrophotometric evidence. The GM5 fraction was composed of two epimeric isomers, and their structures were characterized by (1)H NMR, (1)H-(1)H COSY, (13)C NMR, and HMQC and HMBC spectral measurements.