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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.
AuthorsGuillermo Schmeda-Hirschmann, Jaime A Rodríguez, Cristina Theoduloz, Jaime A Valderrama
JournalPlanta medica (Planta Med) Vol. 77 Issue 4 Pg. 340-5 (Mar 2011) ISSN: 1439-0221 [Electronic] Germany
PMID20862639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© Georg Thieme Verlag KG Stuttgart · New York.
Chemical References
  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Amides
  • Amino Acids
  • Anti-Ulcer Agents
  • Antineoplastic Agents, Phytogenic
  • Diterpenes
  • Plant Extracts
  • imbricatolic acid
  • Lansoprazole
  • Ethanol
  • Hydrochloric Acid
Topics
  • 2-Pyridinylmethylsulfinylbenzimidazoles (pharmacology)
  • Adenocarcinoma (drug therapy)
  • Amides (chemical synthesis, pharmacology, therapeutic use)
  • Amino Acids (chemical synthesis, pharmacology, therapeutic use)
  • Animals
  • Anti-Ulcer Agents (chemical synthesis, pharmacology, therapeutic use)
  • Antineoplastic Agents, Phytogenic (chemical synthesis, pharmacology, therapeutic use)
  • Cell Line
  • Cell Line, Tumor
  • Cycadopsida (chemistry)
  • Disease Models, Animal
  • Diterpenes (isolation & purification, pharmacology, therapeutic use)
  • Ethanol
  • Fibroblasts (drug effects)
  • Humans
  • Hydrochloric Acid
  • Isomerism
  • Lansoprazole
  • Liver Neoplasms (drug therapy)
  • Male
  • Mice
  • Phytotherapy
  • Plant Extracts (chemical synthesis, pharmacology, therapeutic use)
  • Stomach (drug effects, pathology)
  • Stomach Neoplasms (drug therapy)

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