Gastroprotective effect and cytotoxicity of semisynthetic jatropholone derivatives.
The gastroprotective effect of the diterpenes jatropholone A, jatropholone B and 16 semisynthetic derivatives was assessed in the HCl/ethanol-induced gastric lesion model in mice and the cytotoxicity was determined towards fibroblasts and AGS cells. In a dose-response study, jatropholone B reduced gastric lesions by 65% at 6 mg/kg and jatropholone A by 54% at 100 mg/kg. The jatropholone B derivatives 9 - 14 and the compounds 15 - 18 were compared at a single oral dose of 25 mg/kg while the jatropholone A derivatives 2 - 7 were assessed at 100 mg/kg. A decrease in gastroprotective activity was observed for the ether as well as for the ester derivatives of jatropholone B. The methyl and propyl ethers of jatropholone A were more gastroprotective than the natural product. The placement of an additional methyl group at C-2 in the jatropholone B derivatives led to a loss of selectivity, the methyl and propyl ethers lack a gastroprotective effect. Jatropholone B was not toxic towards AGS cells and fibroblasts. Jatropholone A was active only against AGS cells. The gastroprotective effect of the epimeric jatropholones was selective showing a higher effect for jatropholone B. These results further support that the stereochemistry of the methyl group at C-2 in the jatropholones plays a relevant role in preventing the gastric lesions in mice. The compounds 3, 5 - 7, 10 and 12 - 18 are described for the first time.
Pertino
Mariano
M
Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile.
Schmeda-Hirschmann
Guillermo
G
Rodríguez
Jaime A
JA
Theoduloz
Cristina
C
D000284:Administration, Oral; D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004224:Diterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D031286:Jatropha; D008297:Male; D051379:Mice; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D027343:Rhizome; D013270:Stomach / Q000166:cytology / Q000187:drug effects; D013276:Stomach Ulcer / Q000517:prevention & control
D000897:Anti-Ulcer Agents; D004224:Diterpenes; D010936:Plant Extracts; C524033:jatropholone A; C524034:jatropholone B