title: Gastroprotective effect and cytotoxicity of labdenamides.
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 microM. 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 microM towards AGS cells and 10-37 microM towards fibroblasts, respectively.
authors.affiliation: Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile.
authors.forename: Rafael
authors.initials: R
authors.lastname: Izquierdo
authors.forename: Luis
authors.initials: L
authors.lastname: Astudillo
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Rodríguez
authors.forename: Cristina
authors.initials: C
authors.lastname: Theoduloz
authors.forename: José A
authors.initials: JA
authors.lastname: Palenzuela
authors.forename: Guillermo
authors.initials: G
authors.lastname: Schmeda-Hirschmann
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured / Q000187:drug effects; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D000431:Ethanol; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006851:Hydrochloric Acid; D020128:Inhibitory Concentration 50; D008168:Lung / Q000166:cytology; D008297:Male; D051379:Mice; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013270:Stomach / Q000166:cytology; D013276:Stomach Ulcer / Q000139:chemically induced / Q000517:prevention & control*; D064028:Tracheophyta
chemical_list: D000897:Anti-Ulcer Agents; D004224:Diterpenes; D010936:Plant Extracts; D000431:Ethanol; D006851:Hydrochloric Acid