New Gastroprotective Labdeneamides from (4S, 9R, 10R) Methyl 18-carboxy-labda-8,13(E)-diene-15-oate

Abstract

Starting from the diterpene (4S, 9R, 10R) methyl 18-carboxy-labda-8,13(E)-dien-15-oate (PMD) and its 8(9)-en isomer [PMD 8(9)-en], 11 amides were prepared and assessed for a gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice. Basal cytotoxicity of the compounds was determined on the following human cell lines: normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). All compounds are described for the first time. At the single oral dose of 0.1mg/kg, compounds 1, 10, and 11 presented a strong gastroprotective effect, at least comparable with that of the reference compound lansoprazole at 1mg/kg, reducing gastric lesions by 76.7, 67.7, and 77.2%, respectively. The leucyl amide methyl ester 3, tryptophanyl amide methyl ester 5, and benzyl amide 6 of PMD presented a selective basal cytotoxicity on Hep G2 cells with IC50 values of 136.8, 105.3, and 94.2 mu M, respectively, while the IC50 values towards AGS cells were 439.5, 928.0, and 937.3 mu M, respectively. The three compounds did not affect fibroblast viability with IC50 values > 1000 mu M. Compounds 7, 8, 10, and 11 showed no toxic effect against the three selected cell lines.