Jatrophane Diterpenes from Euphorbia esula as Antiproliferative Agents and Potent Chemosensitizers to Overcome Multidrug Resistance

Abstract

Phytochemical study of whole, undried plants of Euphorbia esula led to the isolation of six new (1-6) jatrophane diterpene polyesters, named esulatins H-M, together with the known compounds 2α,3β,5α,7β,15β-pentaacetoxy-9α-nicotinoyloxyjatropha-6(17),11-dien-14-one (7), salicinolide (8), and euphosalicin (9). The structures and relative configuration of 1-6 were established on the basis of extensive spectroscopic analysis, including HRESIMS and one- and two-dimensional NMR techniques. All these compounds, together with diterpenes (10-14) isolated previously from this plant, were evaluated for their antiproliferative activity against HeLa, Ishikawa, and MCF7 cells. The multidrug-resistance-reversing activities were also investigated on L5178 mouse lymphoma cells transfected with the pHa MDR1/A retrovirus DNA. Preliminary structure-activity relationship data are discussed.

Jatrophane and rearranged jatrophane-type diterpenes: biogenesis, structure, isolation, biological activity and SARs (1984–2019)

“…Weak P-gp inhibition was exhibited by 480 and 481 with IC 50 of 8.55 ± 3.21 lM and 8.72 ± 3.45, respectively comparing to cyclosporine A (CsA) (IC 50 of 3.37 ± 1.39 lM) (Lanzotti et al 2015). This finding is in agreement with previous SAR studies on jatrophane diterpenes indicating that the presence of both acylation at C-3 and hydroxylation or acylation at C-5 is detrimental for P-gp reversal activity (Corea et al 2009) and a keto group at C-9 is rather an important feature for cytotoxicity (Vasas et al 2011). In another study, Barile and Lanzotti isolated presegetanin 16 as well as segetanin A and B (10 and 11), along with four known segetanes (86-89) from E. paralias.…”

“…Within the compounds investigated, esulatin J (129) (FAR = 52.5 at 40 lg/mL) and esulatin M (134) (FAR = 119.9 at 40 lg/mL) were found to be the most powerful inhibitors of efflux pump activity. Their efficacy was 25-fold higher than that of positive control 'verapamil' (FAR = 23.2 at 10 lg/mL); thus, both 185 and 188 appeared to be promising leads for drug development to overcome the MDR of cancer cells (Vasas et al 2011). Aljancic et al (2011) investigated the sensitivity of NCI-H460/R cells to another anticancer chemotherapeutic agent, doxorubicin, in the presence of six new jatrophanes, euphodendrophanes A-F (396-400, and 237) from E. dendroides.…”

“…Jatrophane diterpenes occur generally in form of polyesters. They are mainly polyacylated derivatives whose number of ester moieties is ranging between three (guyonianin E) (Hegazy et al 2010) and eight (esulatin H) (Vasas et al 2011). The acyl residues are frequently acetyl, propionyl, butanoyl, isobutanoyl, 2-methylbutanoyl, angeloyl, tigloyl, benzoyl, nicotinoyl, or rarely cinnamoyl.…”

“…Vasas et al (2011) isolated esulatins A-E (374, 470, 92, 382, and 504) and H-M (99, 128, 129, and 132-134) from E. esula. They were evaluated for their antiproliferative activity against a set of human adherent cell lines of gynecological origin (HeLa (cervix adenocarcinoma), Ishikawa (endometrial adenocarcinoma), and MCF-7 (breast epithelial adenocarcinoma)) using the MTT test and 'cisplatin' as positive control (Vasas et al 2011 J, B and E (128, 129, 470, and 504) are tetra-or penta-esters of jatrophane polyols, which contain a keto group at C-9. Moreover, esulatin A (374), containing an epoxy group at C-11-C-12, found also to be effective against all three cell lines.…”

Chemical constituents ofEuphorbia tangutica

“…Detailed study of the profile of secondary metabolites could contribute to taxonomic subdivision of this complex genus. Many secondary metabolites with specific types of diterpene skeleton in the genus have been found to possess a number of interesting biological activities (Ahmad et al, 2005;Lal, Cambie, Rutledge, & Woodgate, 1990;Ravikanth et al, 2002;Vasas et al, 2011), especially antioxidant (Basma, Zakaria, Latha, & Sasidharan, 2011), anti-HBV (Tian, Sun, Li, Liu, & Dong, 2011a), anticancer (Kumar, Sun, Li, Liu, & Dong, 2011;Mayur, Ravirajsinh, Menaka, Ranjitsinh, & Sonal, 2011;Milica et al, 2011) and antiviral activities (Kumar et al, 2011). Euphorbia tangutica Proch., a perennial herbaceous plant, with a milky juice in the aerial part and roots, is distributed mainly in Qinghai and Gansu provinces of China (Liu, 1999).…”