Jatrophane diterpenes from Euphorbia spp. as modulators of multidrug resistance in cancer therapy

Abstract

A phytochemical investigation of the aerial parts of Euphorbia spp., considered one of the most common elements of Mediterranean landascape, led to the isolation of a large number of bioactive plant metabolites, belonging to the diterpenes family. Above all, over seventy jatrophane, modified jatrophane, segetane, pepluane, and paraliane diterpenoids, fifty of them reported for the first time, were extracted, purified and characterized from Euphorbia dendroides, Euphorbia characias, Euphorbia peplus, Euphorbia paralias and Euphorbia helioscopia. These compounds showed interesting pharmacological activities. In particular, jatrophanes, modified jatrophanes and lathyranes exhibited a potent inhibitory activity against P-glycoprotein (Pgp), a membrane protein that confers cellular ability to resist lethal doses of certain cytotoxic drugs by pumping them to the outside, thus resulting in a reduced cytotoxicity. Among the others, our chemical survey led to isolation of the most powerful inhibitors of daunomycin-efflux activity isolated to date for this class of inhibitors, named euphodendroidin D and pepluanin A. Their efficiency was found to be at least two-fold higher than the conventional modulator cyclosporin A, taken as a reference. In addition, the isolation of a high number of natural structurally-related analogues allowed us to perform Structure Activity Relationship (SAR) studies, without any chemical modification, which gave information on the key pharmacophoric elements of these new class of promising drugs. A further set of diterpene analogues, very recently isolated from sun spurge, E. helioscopia, individually investigated for their Pgp-and BCRP-inhibiting properties, appeared to be specific inhibitors of Pgp since they showed no significant activity against BCRP, thus resembling to the third-generation class of specific MDR inhibitors.

Production of Bioactive Diterpenoids in the Euphorbiaceae Depends on Evolutionarily Conserved Gene Clusters

“…Prostratin (a tigliane), which is produced by Homalanthus nutans, Euphorbia fischeriana, and Euphorbia cornigera, has shown potential as an adjuvant therapy for the treatment of latent HIV infection (Miana et al, 1985;Qing-Gao et al, 1997;Kulkosky et al, 2001;Johnson et al, 2008). The jatrophane esters, which are produced by a number of Jatropha and Euphorbia species, have been shown to inhibit p-glycoprotein transporters responsible for efflux of chemotherapeutic agents and may therefore be useful for the treatment of multidrug resistant cancers (Corea et al, 2009;Reis et al, 2012). Jatrophone from Jatropha isabelli has antiplasmodial activity (Hadi et al, 2013).…”

New macrocyclic diterpenes fromEuphorbia connataBoiss. with cytotoxic activities on human breast cancer cell lines

“…Among them, jatrophane-and myrsinane-type compounds are reported in this study. Jatrophanes are modulators of multidrug resistance in cancer therapy (Corea et al 2009). Myrsinanes have been found to possess cytotoxic, spasmolytic immunosuppressive and antiangiogenic activities which made them useful in the treatment of various diseases (Li et al 2010;Ghanadian et al 2014;Ghanadian, Ayatollahi, Mesaik, et al 2013;Ghanadian, Ayatollahi, Afsharypuor, et al 2013).…”

New perspectives on the use of nucleic acids in pharmacological applications: inhibitory action of extracellular self-DNA in biological systems

“…Analogues of lead compounds isolated from nature are synthesized and tested with the aim of finding the best candidate for drug development with more potent activity and reduced side-effects. This step in the pharmacological research is the quantitative structure-activity relationship (QSAR) (Corea et al 2005(Corea et al , 2009Barile et al 2007). …”