Gastroprotective effect and cytotoxicity of labdenamides

Some 18 aromatic amides from the labdane diterpenes 15-acetoxyimbricatolic acid and 15-acetoxylabd-8(9)-en-19-oic acid were prepared and assessed for their gastroprotective effect in the HCl/EtOH-induced gastric lesion model in mice. The analysis of the gastroprotective activity of the benzylamides belonging to the series 8(9)- and 8(17)-ene was undertaken at doses of 12.5, 25 and 50 mg/kg in the HCl/EtOH-induced gastric lesion model in mice. A statistically significant gastroprotective effect was observed for 15-acetoxylabd-8(9)-en-19-oic acid benzylamide starting at 12.5 mg/kg, reducing the gastric lesions by 50%, while 15-acetoxylabd-8(17)-en-19-oic acid benzylamide reduced lesions by 66% at 25 mg/kg. The 25 mg/kg dose was used for the comparison of the different amides. At 25 mg/kg, the highest gastroprotective effect was observed for the benzyl- and 3-bromophenylamides from 15-acetoxyimbricatolic acid as well as for the benzyl- and P-toluidylamides of 15-acetoxylabd-8(9)-en-19-oic acid, being as active as lansoprazole at 20 mg/kg. Most compounds displayed low toxicity against epithelial gastric (AGS) and human lung fibroblasts cells, with IC50 values>1000 microM. The highest cytotoxicity towards AGS cells was observed for the 2-bromophenyl- and 2-hydroxy-5-chlorophenylamides in both diterpene series, with IC50 values in the range of 14-34 microM towards AGS cells and 10-37 microM towards fibroblasts, respectively.