Gastroprotective Effect and Cytotoxicity of Natural and Semisynthetic Labdane Diterpenes from Araucaria araucana Resin

Abstract

The resin of the tree Araucaria araucana (Araucariaceae) is used by the Mapuche Amerindians in southern Chile and Argentina to treat ulcers and has been shown to display a gastroprotective effect in animal models. A study was undertaken to isolate, identify and assess the gastroprotective effect of the resin constituents and its semisynthetic derivatives as well as to evaluate the cytotoxicity of the products in cell cultures. Eleven diterpenes (ten labdane and a pimarane) were isolated from a resin sample collected in Chile. The labdane derivatives 15-acetoxylabd-8(17)-en-19-ol as well as 15,19-diacetoxylabd-8(17)-en are reported for the first time as natural products. Six diterpenes previously described from other plant sources are reported for the first time for the A. araucana resin. The structure of all compounds was elucidated by spectroscopic means. Some 24 diterpenes isolated/prepared in amounts over 10 mg were evaluated for gastroprotective effects in the ethanol/HCl-induced ulcer model in mice at 100 mg/kg. The highest gastroprotective activities were provided by 15-hydroxyimbricatolal, 15-acetoxyimbricatolal, 15-acetoxylabd-8(17)-en-19-oic acid methyl ester and 15-acetoxy-19-labdanoic acid, all of them being as active as the reference drug lansoprazole at 20 mg/kg. The cytotoxicity of 30 diterpenes as well as lansoprazole was assessed towards human lung fibroblasts (MRC-5) and 26 compounds were evaluated on the human gastric epithelial cell line AGS by means of the neutral red uptake assay. A concentration-dependent cell viability inhibition was found with IC 50 values ranging from 27 up to > 1000 µm. The relationship between the cytotoxicity data and lipophilicity of the products is also discussed.

Biotransformations of Imbricatolic Acid by Aspergillus niger and Rhizopus nigricans Cultures

“…Compound 1 presented cytotoxicity IC 50 values of 134 and 280 µM towards AGS cells and fibroblasts, respectively [2]. The cytotoxicity of the derivative 3 (IC 50 values) was previously reported as 288 and 305 µM towards AGS cells and fibroblasts, respectively [2]. Mycophenolic acid (4) and its derivative 5 showed low cytotoxicity with IC 50 values > 1000 µM against AGS cells and fibroblasts.…”

“…Fractions 7-8 eluted with EtOAc (200 mL) and 9-10 (EtOAc-MeOH 9:1, 200 mL) afforded a mixture of imbricatolic acid (1) and a second, more polar compound which gave a red-violet spot with anisaldehyde-sulphuric acid reagent. Preparative TLC of the combined fractions 7-10 (silica gel, PE-EtOAc 1:1) afforded 60 mg of imbricatolic acid (1) and 30 mg of 15-hydroxy-8,17-epoxylabdan-19-oic acid (3) [2].…”

“…Koch. The resin, as well as imbricatolic acid, have been recently shown to display gastroprotective effects in induced gastric lesion models in animals [1,2]. The gastroprotective effect of several semisynthetic derivatives of imbricatolic acid was assessed, but so far none of them contained hydroxy functions in the A ring.…”

Diterpenylquinone Hybrids: Synthesis and Assessment of Gastroprotective Mechanisms of Action in Human Cells

“…The quinone part of the molecule included an isoprenyl side chain, hydrogenated side chains with aromatic rings in the naphthoquinone moiety or hydrogenated side chains and aromatic rings. The diterpene junicedric acid (4) with an exocyclic double bond, its isomer 5 with an Δ8(9) double bond and the hydrogenation product 6 were used as the terpene part of the hybrid molecules. Eighteen hybrids, including six new compounds, were synthesized (Scheme 1), differing in some structural features while maintaining common characteristics to evaluate structure-activity trends.…”

“…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 then incorporated into Paraguayan folk medicine, to treat cancer and wounds [2]. The naphthoquinone lapachol from Tabebuia species [3] and labdane diterpenes from A. araucana, display gastroprotective activity in vivo [4] supporting the ethnobotanical information. The bioactive compounds from those crude drugs (quinones and diterpenes) exert their effect as single chemical entities.…”