Diterpenylquinone hybrids: synthesis and assessment of gastroprotective mechanisms of action in human cells

• Published in: Molecules (Basel, Switzerland) Switzerland), 2013-09, Vol.18 (9), p.11044-11066
• Main Authors: Theoduloz, Cristina, Bravo, Ivanna, Pertino, Mariano Walter, Schmeda-Hirschmann, Guillermo
• Format: Article
• Language: English
• Subjects: Cell culture; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytoprotection; Cytotoxicity; Dinoprostone - metabolism; Diterpenes - chemical synthesis; Diterpenes - pharmacology; diterpenylquinones; Drug Evaluation, Preclinical; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Gastric Mucosa - pathology; gastroprotection; Glutathione - metabolism; human cells; Humans; hybrid compounds; Hydrogenation; Inhibitory Concentration 50; labdane diterpenes; Laboratory animals; lapachol; Lipid Peroxidation - drug effects; Primary Cell Culture; Quinones - chemical synthesis; Quinones - pharmacology; Stomach - pathology; Stomach Ulcer - drug therapy; Trends
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules180911044

A modern approach in the search for new bioactive molecules is the synthesis of novel chemical entities combining molecules of different biosynthetic origin presenting biological effects as single compounds. Gastroprotective compounds from South American medicinal plants, namely quinones and diterpenes, were used as building blocks to obtain hybrid diterpenylquinones. Starting from the labdane diterpene junicedric acid and two isomers, as well as from three quinones, including lapachol, 18 hybrid molecules were synthesized. Six of them are described for the first time. The potential gastroprotective mechanisms of action of the compounds were assessed in dose-response experiments using human gastric epithelial cells (AGS) and human lung fibroblasts (MRC-5). The following studies were carried out: stimulation of cell proliferation, cytoprotection against sodium taurocholate (NaT)-induced damage, synthesis of PGE2 and total reduced sulfhydryl (GSH) content. The antioxidant capacity of the compounds was determined on the inhibition of the lipoperoxidation in human erythrocyte membranes. Hybrid compounds presented activities different from those shown by the starting compounds, supporting the potential of this approach in the search for new bioactive molecules. The effects might be modulated by selective modification in the terpene or quinone moieties of the new molecules. Structure-activity relationships are discussed.