New Gastroprotective Labdeneamides from (4S,9R,10R) Methyl 18-carboxy-labda-8,13(E)-diene-15-oate Article - 2012

Verónica Olate, Mariano Pertino, Cristina Theoduloz, Erdem Yesilada, Francisco Monsalve, Paulo González, Daniel Droguett, Pascal Richomme, A.-Hamid-A. Hadi, Guillermo Schmeda-Hirschmann

Verónica Olate, Mariano Pertino, Cristina Theoduloz, Erdem Yesilada, Francisco Monsalve, Paulo González, Daniel Droguett, Pascal Richomme, A.-Hamid-A. Hadi, Guillermo Schmeda-Hirschmann, « New Gastroprotective Labdeneamides from (4S,9R,10R) Methyl 18-carboxy-labda-8,13(E)-diene-15-oate  », Planta Medica, 2012, pp. 362 - 367. ISSN 0032-0943

Abstract

<p>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 0.1 mg/kg, compounds 1, 10, and 11 presented a strong gastroprotective effect, at least comparable with that of the reference compound lansoprazole at 1 mg/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 IC<sub>50</sub> values of 136.8, 105.3, and 94.2 µM, respectively, while the IC<sub>50 </sub>values towards AGS cells were 439.5, 928.0, and 937.3 µM, respectively. The three compounds did not affect fibroblast viability with IC<sub>50</sub> values &gt ; 1000 µM. Compounds 7, 8, 10, and 11 showed no toxic effect against the three selected cell lines.</p>

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