Gastroprotective Effect and Cytotoxicity of Labdeneamides with Amino Acids
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Date
2011
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GEORG THIEME VERLAG KG
Abstract
Semisynthetic aromatic amides from Araucaria araucana diterpene acids have been shown to display a relevant gastroprotective effect with low cytotoxicity. The aim of this work was to assess the gastroprotective effect of amino acid amides from imbricatolic acid and its 8(9)-en isomer in the ethanol/HCl-induced gastric lesions model in mice as well as to determine the cytotoxicity of the obtained compounds on the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma (AGS), and liver hepatocellular carcinoma (Hep G2). The diterpenes 15-acetoxyimbricatolic acid, its 8(9)-en isomer, 15-hydroxyimbricatolic acid, and the 8(9)-en derivative, bearing a COOH function at C-19, were used as starting compounds. New amides with C-protected amino acids were prepared. The study reports the effect of a single oral administration of either compound 50 min before the induction of gastric lesions by ethanol/HCl. Some 20 amino acid monoamides were obtained. Dose-response experiments on the glycyl derivatives showed that at a single oral dose of 100 mg/kg, the compounds presented an effect comparable to the reference drug lansoprazole at 20 mg/kg and at 50 mg/kg reduced gastric lesions by about 50%. All derivatives obtained in amounts >30 mg were compared at a single oral dose of 50 mg/kg. The best gastroprotective effect was observed for the exomethylene derivatives bearing a valine residue at C-19 either with an acetoxy or free hydroxy group at C-15. The tryptophanyl derivative from the acetate belonging to the 8,9-en series presented selective cytotoxicity against hepatocytes. The glycyl amide of 15-acetoxyimbricatolic acid was the most cytotoxic and less selective compound with IC50 values between 47 and 103 mu M for the studied cell lines. This is the first report on the obtention of semisynthetic amino acid amides from labdane diterpenes.
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Keywords
amino acid amides, Araucaria araucana, Araucariaceae, cytotoxicity, gastroprotective effect, labdane diterpenes, ARAUCARIA-ARAUCANA RESIN, INDUCED GASTRIC-LESIONS, SALVINORIN-A ANALOGS, ANTIULCER ACTIVITY, CROTON-CAJUCARA, MONOSODIUM SALT, DERIVATIVES, SOLIDAGENONE, RATS, ULCER