Planta Med 2011; 77(4): 340-345
DOI: 10.1055/s-0030-1250323
Biological and Pharmacological Activity
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Gastroprotective Effect and Cytotoxicity of Labdeneamides with Amino Acids

Guillermo Schmeda-Hirschmann1 , Jaime A. Rodríguez2 [*] , Cristina Theoduloz2 , Jaime A. Valderrama3
  • 1Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile
  • 2Depto. de Bioquímica Clínica, Facultad de Ciencias de la Salud, Universidad de Talca, Talca, Chile
  • 3Depto. de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile
Further Information

Publication History

received May 3, 2010 revised August 2, 2010

accepted August 12, 2010

Publication Date:
22 September 2010 (eFirst)

Abstract

Semisynthetic aromatic amides from Araucaria araucana diterpene acids have been shown to display a relevant gastroprotective effect with low cytotoxicity. The aim of this work was to assess the gastroprotective effect of amino acid amides from imbricatolic acid and its 8 (9)-en isomer in the ethanol/HCl-induced gastric lesions model in mice as well as to determine the cytotoxicity of the obtained compounds on the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma (AGS), and liver hepatocellular carcinoma (Hep G2). The diterpenes 15-acetoxyimbricatolic acid, its 8 (9)-en isomer, 15-hydroxyimbricatolic acid, and the 8 (9)-en derivative, bearing a COOH function at C-19, were used as starting compounds. New amides with C-protected amino acids were prepared. The study reports the effect of a single oral administration of either compound 50 min before the induction of gastric lesions by ethanol/HCl. Some 20 amino acid monoamides were obtained. Dose-response experiments on the glycyl derivatives showed that at a single oral dose of 100 mg/kg, the compounds presented an effect comparable to the reference drug lansoprazole at 20 mg/kg and at 50 mg/kg reduced gastric lesions by about 50 %. All derivatives obtained in amounts > 30 mg were compared at a single oral dose of 50 mg/kg. The best gastroprotective effect was observed for the exomethylene derivatives bearing a valine residue at C-19 either with an acetoxy or free hydroxy group at C-15. The tryptophanyl derivative from the acetate belonging to the 8,9-en series presented selective cytotoxicity against hepatocytes. The glycyl amide of 15-acetoxyimbricatolic acid was the most cytotoxic and less selective compound with IC50 values between 47 and 103 µM for the studied cell lines. This is the first report on the obtention of semisynthetic amino acid amides from labdane diterpenes.

References

1 Dedicated to the memory of Prof. Dr. Jaime A. Rodríguez

G. Schmeda-Hirschmann

Laboratorio de Química de Productos Naturales
Instituto de Química de Recursos Naturales
Universidad de Talca

Casilla 747

Talca

Chile

Phone: +56 71 20 02 88

Fax: +56 71 20 15 73

Email: schmeda@utalca.cl