title: Gastroprotective effect and cytotoxicity of labdeneamides with amino acids.
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 µM for the studied cell lines. This is the first report on the obtention of semisynthetic amino acid amides from labdane diterpenes.
authors.affiliation: Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile. schmeda@utalca.cl
authors.forename: Guillermo
authors.initials: G
authors.lastname: Schmeda-Hirschmann
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Rodríguez
authors.forename: Cristina
authors.initials: C
authors.lastname: Theoduloz
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Valderrama
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology; D000230:Adenocarcinoma / Q000188:drug therapy; D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000596:Amino Acids / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D032462:Cycadopsida / Q000737:chemistry*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D000431:Ethanol; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006851:Hydrochloric Acid; D007536:Isomerism; D064747:Lansoprazole; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008517:Phytotherapy; D010936:Plant Extracts / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D013270:Stomach / Q000187:drug effects* / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000577:Amides; D000596:Amino Acids; D000897:Anti-Ulcer Agents; D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D010936:Plant Extracts; C524691:imbricatolic acid; D064747:Lansoprazole; D000431:Ethanol; D006851:Hydrochloric Acid