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Synthesis, Gastroprotective Effect and Cytotoxicity of New Amino Acid Diterpene Monoamides and Diamides†
Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile
Laboratorio de Cultivo Celular, Departamento de Bioquímica Clínica, Facultad de Ciencias de la Salud, Universidad de Talca, Talca, Chile
Departamento de Ciencias Básicas, Facultad de Ciencias de la Salud, Universidad de Talca, Talca, Chile
Departamento de Estomatología, Facultad de Ciencias de la Salud, Universidad de Talca, Talca, Chile
† Dedicated to the memory of Professor Jaime A. Rodriguez
* Author to whom correspondence should be addressed.
Received: 9 August 2010; in revised form: 5 October 2010 / Accepted: 14 October 2010 / Published: 21 October 2010
Abstract: Following our studies on the gastroprotective effect and cytotoxicity of terpene derivatives, new amides were prepared from the diterpene 8(17)-labden-15,19-dioic acid (junicedric acid) and its 8(9)-en isomer with C-protected amino acids (amino acid esters). The new compounds were evaluated for their gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice, as well as for cytotoxicity using the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma cells (AGS) and liver hepatocellular carcinoma (Hep G2). A dose-response experiment showed that at 25 mg/kg the C-15 leucyl and C-15,19-dileucylester amides of junicedric acid reduced gastric lesions by about 65.6 and 49.6%, respectively, with an effect comparable to lansoprazole at 20 mg/kg (79.3% lesion reduction). The comparison of the gastroprotective effect of 18 new amino acid ester amides was carried out at a single oral dose of 25 mg/kg. Several compounds presented a strong gastroprotective effect, reducing gastric lesions in the 70.9-87.8% range. The diprolyl derivative of junicedric acid, the most active product of this study (87.8% lesion reduction at 25 mg/kg) presented a cytotoxicity value comparable with that of the reference compound lansoprazole. The structure-activity relationships are discussed.
Keywords: labdane diterpenes; amino acid ester amides; gastroprotective effect; cytotoxicity
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Schmeda-Hirschmann, G.; Pertino, M.W.; Rodriguez, J.A.; Monsalve, F.; Droguett, D.; Theoduloz, C. Synthesis, Gastroprotective Effect and Cytotoxicity of New Amino Acid Diterpene Monoamides and Diamides. Molecules 2010, 15, 7378-7394.
Schmeda-Hirschmann G, Pertino MW, Rodriguez JA, Monsalve F, Droguett D, Theoduloz C. Synthesis, Gastroprotective Effect and Cytotoxicity of New Amino Acid Diterpene Monoamides and Diamides. Molecules. 2010; 15(10):7378-7394.
Schmeda-Hirschmann, Guillermo; Pertino, Mariano Walter; Rodriguez, Jaime A.; Monsalve, Francisco; Droguett, Daniel; Theoduloz, Cristina. 2010. "Synthesis, Gastroprotective Effect and Cytotoxicity of New Amino Acid Diterpene Monoamides and Diamides." Molecules 15, no. 10: 7378-7394.