Gastroprotective and cytotoxic effect of dehydroabietic acid derivatives.
Dehydroabietic acid derivatives have been reported to display antisecretory and antipepsin effect in animal models. Some 19 dehydroabietic acid diterpenes were prepared and assessed for gastroprotective activity in the HCl/EtOH-induced gastric lesions in mice as well as for cytotoxicity in human lung fibroblasts (MRC-5) and human epithelial gastric (AGS) cells. At a single oral dose of 100 mg kg(-1), highest gastroprotective effect was provided by dehydroabietanol, its corresponding aldehyde, dehydroabietic acid (DHA) and its methyl ester, N-(m-nitrophenyl)-, N-(o-chlorophenyl)- and N-(p-iodophenyl)abieta-8,11,13-trien-18-amide (compounds 12-14), N-2-aminothiazolyl- and N-benzylabieta-8,11,13-trien-18-amide (compounds 18-19) being as active as lansoprazole at 20 mg kg(-1) and reducing the lesion index by at least 75%. In the compound series including the alcohol, ester, aldehyde, acid and methyl ester at C-18 (compounds 1-9), highest activity was related with the presence of an alcohol, aldehyde, acid or methyl ester at C-18, the activity being strongly reduced after esterification. The cytotoxicity of the compounds 1-9 towards AGS cells and fibroblasts was higher than the values for the amides 10-19. In the compounds 10-19, the best gastroprotective effect was observed for the aromatic amides 12-14 (75-85% inhibition of gastric lesions) bearing a nitro or halogen function in the N-benzoyl moiety. Lowest cytotoxicity was found for the amides, with IC(50) values >1000 microM for fibroblasts and from 200 up to >1000 microM for AGS cells, respectively. The N-2-aminothiazolyl- and N-benzylamide derivatives were also very active as gastroprotectors with higher cytotoxicity against AGS cells.
Sepúlveda
Beatriz
B
Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile.
Astudillo
Luis
L
Rodríguez
Jaime A
JA
Yáñez
Tania
T
Theoduloz
Cristina
C
Schmeda-Hirschmann
Guillermo
G
D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship
D045784:Abietanes; D004224:Diterpenes; C013913:dehydroabietic acid