Diterpenes from Euphorbia as Potential Leads for Drug Design

Abstract

In the course of our chemical survey of bioactive plant metabolites, a large number of diterpenes have been isolated from Euphorbia species that showed interesting pharmacological activities. In particular, over sixty jatrophane, modified jatrophane, segetane, pepluane, and paraliane diterpenoids, fifty of them reported for the first time, were extracted, purified and characterized from Euphorbia dendroides, E. characias, E. peplus, E. amygdaloides, and E. paralias. The compounds based on jatrophane and modified jatrophane skeletons were shown to be potent inhibitors of P-glycoprotein, a membrane protein that confers upon cells the ability to resist lethal doses of certain cytotoxic drugs by pumping them out of the cells, thus resulting in a reduced cytotoxic effect. Those belonging to the rare classes of pepluane and paraliane were shown to be promising anti-inflammatory agents in vivo. In addition, by using LPS-stimulated J774 murine macrophages, it was demonstrated that the effect is ascribable to the reduction in the production of nitric oxide, prostaglandin E₂ and TNF-α by inhibiting the expression of inducible nitric oxide synthase, cyclooxygenase-2 and TNF-α mRNA, respectively, through the down-regulation of NF-κB binding activity. The isolation of structurally-related analogues allowed us to perform SAR studies, which gave information on the key pharmacophoric elements of these new classes of promising drugs.