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-methylbenzofuran-2-carbonyl
ester ( 12), ferruginyl
indoleacetate ( 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 (IC (50) values of 12, 22 and 29 microM, respectively). The isobutyrate 4, inactive as a gastroprotective agent, showed selective cytotoxicity against AGS and Hep G2 cells (IC (50) values of 60 and 39.2 microM, respectively). The cytotoxicity of the above cited compounds towards fibroblasts was >1000 microM. Considering the aliphatic
esters of
ferruginol, the best gastroprotective activity was found in the C (16) and C (18) 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 (
indoleacetate and
nicotinate) or nitro group (3,5-dinitrobenzoate).