Abstract
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.
Highlights
South American traditional medicine uses plants in therapeutic practice
Little has been done on the synthesis of products combining naturally occurring moieties arising from different biosynthetic pathways into such hybrid molecules
A series of hybrid compounds was synthesized using as building blocks diterpenes and quinones
Summary
South American traditional medicine uses plants in therapeutic practice. Several herbal crude drugs have been shown to contain bioactive constituents that can be clearly related to their beneficial effects.The resin of the “araucaria” tree (Araucaria araucana (Mol.) K. The stem bark of the crude drug “lapacho” or “taheebo” (Tabebuia spp., Bignoniaceae) was formerly used by the Guarani as an anti-inflammatory agent and incorporated into Paraguayan folk medicine, to treat cancer and wounds [2]. The bioactive compounds from those crude drugs (quinones and diterpenes) exert their effect as single chemical entities. A new approach in drug design is to combine two different molecules with individual intrinsic effects into a single new hybrid compound [5]. Terpenylquinones have been described from some marine organisms and display several biological activities, including cytotoxicity and anti-inflammatory effect [8]. New hybrid compounds containing terpene and quinone moieties have been prepared and some of them present relevant biological effects including cytotoxicity [9,10] and antifungal effect [11]
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