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.
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Authors | Guillermo Schmeda-Hirschmann, Jaime A Rodríguez, Cristina Theoduloz, Jaime A Valderrama |
Journal | Planta medica
(Planta Med)
Vol. 77
Issue 4
Pg. 340-5
(Mar 2011)
ISSN: 1439-0221 [Electronic] Germany |
PMID | 20862639
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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