title: 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 0.1 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 IC₅₀ values of 136.8, 105.3, and 94.2 µM, respectively, while the IC₅₀ values towards AGS cells were 439.5, 928.0, and 937.3 µM, respectively. The three compounds did not affect fibroblast viability with IC₅₀ values > 1000 µM. Compounds 7, 8, 10, and 11 showed no toxic effect against the three selected cell lines.
authors.affiliation: Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile.
authors.forename: Verónica Rachel
authors.initials: VR
authors.lastname: Olate
authors.forename: Mariano Walter
authors.initials: MW
authors.lastname: Pertino
authors.forename: Cristina
authors.initials: C
authors.lastname: Theoduloz
authors.forename: Erdem
authors.initials: E
authors.lastname: Yesilada
authors.forename: Francisco
authors.initials: F
authors.lastname: Monsalve
authors.forename: Paulo
authors.initials: P
authors.lastname: González
authors.forename: Daniel
authors.initials: D
authors.lastname: Droguett
authors.forename: Pascal
authors.initials: P
authors.lastname: Richomme
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Hadi
authors.forename: Guillermo
authors.initials: G
authors.lastname: Schmeda-Hirschmann
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008168:Lung / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D010936:Plant Extracts / Q000494:pharmacology; D031044:Polyalthia / Q000737:chemistry; D013272:Stomach Diseases / Q000517:prevention & control*; D013274:Stomach Neoplasms / Q000188:drug therapy
chemical_list: D000577:Amides; D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D010936:Plant Extracts; C074987:methyl 18-carboxylabda-8,13-diene-15-oate