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Original Paper
Pharmacology | Planta Med 2007; 73: 310-317
DOI: 10.1055/s-2007-967153 |
© Georg Thieme Verlag KG Stuttgart · New York |
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Gastroprotective Effect and Cytotoxicity of Labdenamides |
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| Rafael Izquierdo2, Luis Astudillo2, Jaime A. Rodríguez3, Cristina Theoduloz3, José A. Palenzuela4, Guillermo Schmeda-Hirschmann1 |
1 Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile
2 Laboratorio de Síntesis Orgánica, Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile
3 Depto. de Ciencias Básicas Biomédicas, Facultad de Ciencias de la Salud, Universidad de Talca, Talca, Chile
4 Centro de Productos Naturales Orgánicos ”Antonio González”, Depto. de Química Orgánica, Facultad de Farmacia, Universidad de La Laguna, Tenerife, Spain |
Abstract
Some 18 aromatic amides from the labdane diterpenes 15-acetoxyimbricatolic acid and 15-acetoxylabd-8(9)-en-19-oic acid were prepared and assessed for their gastroprotective effect in the HCl/EtOH-induced gastric lesion model in mice. The analysis of the gastroprotective activity of the benzylamides belonging to the series 8(9)- and 8(17)-ene was undertaken at doses of 12.5, 25 and 50 mg/kg in the HCl/EtOH-induced gastric lesion model in mice. A statistically significant gastroprotective effect was observed for 15-acetoxylabd-8(9)-en-19-oic acid benzylamide starting at 12.5 mg/kg, reducing the gastric lesions by 50 %, while 15-acetoxylabd-8(17)-en-19-oic acid benzylamide reduced lesions by 66 % at 25 mg/kg. The 25 mg/kg dose was used for the comparison of the different amides. At 25 mg/kg, the highest gastroprotective effect was observed for the benzyl- and 3-bromophenylamides from 15-acetoxyimbricatolic acid as well as for the benzyl- and p-toluidylamides of 15-acetoxylabd-8(9)-en-19-oic acid, being as active as lansoprazole at 20 mg/kg. Most compounds displayed low toxicity against epithelial gastric (AGS) and human lung fibroblasts cells, with IC50 values > 1000 μM. The highest cytotoxicity towards AGS cells was observed for the 2-bromophenyl- and 2-hydroxy-5-chlorophenylamides in both diterpene series, with IC50 values in the range of 14 - 34 μM towards AGS cells and 10 - 37 μM towards fibroblasts, respectively.
Key words
Araucaria araucana - Araucariaceae - labdane derivatives - semisynthetic derivatives - diterpenes - gastroprotective activity - cytotoxicity - human lung fibroblasts - epithelial gastric cells
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