Abstract

The diterpene ferruginol has shown a strong protective effect in animal gastric ulcer models. In the present work, we report the gastroprotective effect and cytotoxicity of 16 new semisynthetic ester derivatives of ferruginol. The gastroprotective effect of these compounds was assessed with the HCl/EtOH-induced gastric lesions model in mice and the cytotoxicity was measured using MRC-5 fibroblasts, gastric adenocarcinoma (AGS) and liver hepatoma Hep G2 cells. The compounds were tested for a gastroprotective effect at a single oral dose of 20 mg/kg. The best gastroprotective effect was elicited by ferruginyl nicotinate (13), reducing the lesion index by 71 %, while the derivatives ferruginyl chloroacetate (2), ferruginyl palmitate (6), ferruginyl oleate (7), ferruginyl 3,5-dinitrobenzoate (11), ferruginyl 3-methyl-benzofuran-2-carbonyl ester (12), ferruginyl in-doleacetate (14), ferruginyl indolebutyrate (15) and ferruginyl pthalate (16) reduced the lesions by 49-66%. The most promising compounds were 11, 13 and 14, presenting a gastroprotective effect higher or similar to that of ferruginol but with a high selectivity towards the tumor AGS cells. Among the three products, the most selective towards AGS cells was 14, followed by 13, and 11 (IC50 values of 12, 22 and 29 μM, respectively). The isobutyrate 4, inactive as a gastroprotective agent, showed selective cytotoxicity against AGS and Hep G2 cells (IC50 values of 60 and 39.2 μM, respectively). The cytotoxicity of the above cited compounds towards fibroblasts was >1000, μM. Considering the aliphatic esters of ferruginol, the best gastroprotective activity was found in the C16 and C18 derivatives but tended to decrease with increasing aliphatic chain unsaturation. For short-chain esters, the gastroprotective effect could be observed when the chain contained a chlorine atom. For aromatic esters, the presence of nitro groups or a nitrogen atom in the aromatic ring enhanced the gastroprotective activity. The compounds with the best gastroprotective effect and the highest selectivity against tumor cells bear an amino group (indo-leacetate and nicotinate) or nitro group (3,5-dinitrobenzoate).