The gastroprotective abietane diterpene ferruginol has been shown to present high cytotoxicity. In order to obtain active compounds with less cytotoxicity, 18 semisynthetic ferruginol derivatives and totarol were assessed for their gastroprotective effects in the HCl/ethanol-induced gastric lesion model in mice, as well as for cytotoxicity in human gastric epithelial cells (AGS) and human lung fibroblasts (MRC-5). At 20 mg kg(-1), the greatest gastroprotective effects were provided by abieta-8,11,13-triene (1), abieta-8,11,13-trien-12-yl-2-chloropropanoate (8), abieta-8,11,13-trien-12-yl propenoate (9), 12-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-abieta-8,11,13-triene (17) and 12-(beta-D-galactopyranosyloxy)-abieta-8,11,13-triene (18), all of which were as active as the reference drug lansoprazole at 20 mg kg(-1), reducing gastric lesions by 69, 76, 67, 72 and 61%, respectively. No relation was observed between lipophilicity and the gastroprotective effect. Compounds that showed the greatest cytotoxicity towards AGS cells were ferruginol (2), the corresponding formate (5), acetate (6), propionate (7), 8, 9, 12-(beta-D-glucopyranosyloxy)-abieta-8,11,13-triene (16), 18 and totarol (20) (IC50 18-44 microM). Ferruginol and compounds 5-9, 16, 18 and 20 were the most toxic compounds against fibroblasts (IC50 19-56 microM), with a correlation to AGS cells. The derivative 19 was much more active against AGS cells than towards fibroblasts. The best activity/cytotoxicity ratio was found for compound 17, with a lesion index comparable with lansoprazole at 20 mg kg(-1) and cytotoxicity >1000 microM towards MRC-5 and AGS cells, respectively. In conclusion, some derivatives showed a better gastroprotective effect/cytotoxicity ratio than the parent compound ferruginol. A total of 13 new compounds are reported here for the first time.