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Molecules 2010, 15(10), 7378-7394; doi:10.3390/molecules15107378
Article

Synthesis, Gastroprotective Effect and Cytotoxicity of New Amino Acid Diterpene Monoamides and Diamides

1,* , 1, 2, 3, 4 and 2
1 Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile 2 Laboratorio de Cultivo Celular, Departamento de Bioquímica Clínica, Facultad de Ciencias de la Salud, Universidad de Talca, Talca, Chile 3 Departamento de Ciencias Básicas, Facultad de Ciencias de la Salud, Universidad de Talca, Talca, Chile 4 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 / Revised: 5 October 2010 / Accepted: 14 October 2010 / Published: 21 October 2010
(This article belongs to the Section Medicinal Chemistry)
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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 labdane diterpenes; amino acid ester amides; gastroprotective effect; cytotoxicity
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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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.

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