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Euphopepluanones F − K (1 − 4), four new jatrophane type diterpenoids were isolated from the seeds of Euphorbia peplus, along with eight known diterpenoids (5 − 12). Their structures were established on the basis of extensive spectroscopic analysis and X-ray crystallographic experiments. The new compounds 1 − 4 were assessed for their activities to induce lysosomal biogenesis through LysoTracker Red staining. Compound 2 significantly induced lysosomal biogenesis. In addition, compound 2 could increase the number of LC3 dots, indicating that it could activate the lysosomal-autophagy pathway. [ABSTRACT FROM AUTHOR]

Macrocyclic diterpenoids produced by plants of the Euphorbiaceae family are of considerable interest due to their high structural diversity; and their therapeutically relevant biological properties. Over the last decade many studies have reported the ability of macrocyclic diterpenoids to inhibit in cellulo the cytopathic effect induced by the chikungunya virus. This review; which covers the years 2011 to 2019; lists all macrocyclic diterpenoids that have been evaluated for their ability to inhibit viral replication. The structure−activity relationships and the probable involvement of protein kinase C in their mechanism of action are also detailed.

We investigated the molecular mechanism of apoptosis induced by novel jatropha-6(17),11 E-diene class derivatives, compounds A, B, and C that were extracted from Euphorbia osyridea Boiss, in the ovarian cancer cell lines Caov-4 and OVCAR-3. The OVCAR-3 and Caov-4 cell lines were treated with different concentrations of these compounds. Cytotoxicity was evaluated using MTT, clonogenic survival assay, and flow cytometry assays. The production of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and the activity of caspase 3 and 9 were evaluated. Compounds A, B, and C reduced cell viability in a dose-dependent manner ( P < 0.05). The IC50 values were calculated as 46.27 ± 3.86, and 38.81 ± 3.30 μmol/L for compound A, 36.48 ± 3.18 and 42.59 ± 4.50 μmol/L for compound B, and 85.86 ± 6.75 and 75.65 ± 2.56 μmol/L for compound C against the Caov-4 and OVCAR-3 cell lines, respectively. Apoptosis evaluation showed that jatrophane derivatives increase both early and late apoptosis ( P < 0.01). These compounds also increased ROS generation, ΔΨm, and the activity of caspase 3 and 9 in the treated cells. These results showed that compounds A and B have significant inhibitory effects on OVCAR-3 and Caov-4 proliferation and induction of apoptosis. [ABSTRACT FROM AUTHOR]

Background: Modulation of P-glycoprotein (ABCB1) and evaluation of the collateral sensitivity effect are among the most promising approaches to overcome multidrug resistance (MDR) in cancer. In a previous study, two rare 12,17-cyclojatrophanes (1-2) and other novel jatrophanes (3-4), isolated from Euphorbia welwitschii, were screened for collateral sensitivity effect. Herein, the isolation of another jatrophane (5) is presented, being the broader goal of this work to investigate the role of euphowelwitschines A (1) and B (2), welwitschene (3), epoxywelwitschene (4) and esulatin M (5) as ABCB1 modulators and/or collateral sensitivity agents.Methods: Compounds 1-5 were evaluated for ABCB1 modulation ability through combination of transport and chemosensitivity assays, using a mouse T-lymphoma MDR1-transfected cell model. Moreover, the nature of interaction of compound 4 with ABCB1 was studied, using an ATPase assay. The MDR-selective antiproliferative activity of compound 5 was evaluated against gastric (EPG85-257) and pancreatic (EPP85-181) human cancer cells and their drug-selected counterparts (EPG85-257RDB, EPG85-257RNOV, EPP85-181RDB, EPP85-181RNOV). The drug induced cell death was investigated for compounds 4 and 5, using the annexin V/PI staining and the active caspase-3 assay.Results: The jatrophanes 1-5 were able to modulate the efflux activity of ABCB1, and at 2µM, 3-5 maintained the strong modulator profile. Structure activity results indicated that high conformational flexibility of the twelve-membered ring of compounds 3-5 favored ABCB1 modulation, in contrast to the tetracyclic scaffold of compounds 1 and 2. The effects of epoxywelwitschene (4) on the ATPase activity of ABCB1 showed it to interact with the transporter and to be able to reduce the transport of a second subtrate. Drug combination experiments also corroborated the anti-MDR potential of these diterpenes due to their synergistic interaction with doxorubicin (combination index <0.7). Esulatin M (5) showed a strong MDR-selective antiproliferative activity against EPG85-257RDB and EPP85-181RDB cells, with IC50 of 1.8 and 4.8 µM, respectively. Compounds 4 and 5 induced apoptosis via caspase-3 activation. A significant discrimination was observed between the resistant cell lines and parental cells.Conclusions: This study strengthens the role of jatrophane diterpenes as lead candidates for the development of MDR reversal agents, higlighting the action of compounds 4 and 5. [ABSTRACT FROM AUTHOR]

This paper reports our effort to develop a comprehensive HPLC-MS n -based dereplication strategy for phorbol ester (PE), deoxyphorbol ester (dPE) and ingenol ester (IE) profiling in plant extracts. This strategy is composed of two sequential analysis exploiting specific hybrid triple quadrupole/linear ion trap instrument modes. A first run was performed using a multiple reaction monitoring (MRM) mode targeting fragmentation of PE and dPE/IE coupled with the acquisition of MS 2 spectrum for the ions at m / z 311 and m/z 313, respectively. A second run was then completed based on precursor ion scan mode (PIS) and automatic MS 2 acquisition for each quasimolecular ion. The developed approach was used to investigate ten Euphorbia extracts showing bioactivity against chikungunya virus replication. Experiments allowed partial annotation of three dPE/IE but no PE was detected. Results suggested that other types of diterpene esters displayed PE- and dPE/IE-like fragmentations. The study of jatrophane ester (JE) standards by CID fragmentation using low and high resolution mass spectrometry confirmed this hypothesis, highlighting challenges and difficulties of diterpene esters profiling within plant extracts. Nonetheless, the present LC–MS n method can be easily adapted to profile other types of diterpene esters. [ABSTRACT FROM AUTHOR]

Three undescribed diterpenes including two ent- abietanes, euphomauritanol A, and euphomauritanol B, and one jatrophane, euphomauritanophane A, in addition to eight previously described metabolites were isolated from the MeOH–CH 2 Cl 2 (1:1) extract of the Euphorbia mauritanica. The chemical structures of isolates were established based on the spectroscopic means including FT-IR, HRMS, 1D and 2D NMR. The absolute stereochemistry of the undescribed diterpenes was deduced by experimental and calculated TDDFT-electronic circular dichroism (ECD). The anti-proliferative effects of the isolated diterpenes were evaluated against B16-BL6, Hep G2, and Caco-2. The euphomauritanol A, euphomauritanol B, and euphomauritanophane A significantly inhibited the growth of murine melanoma B16-BL6 cell lines with IC 50 10.28, 20.22, and 38.81 μM, respectively with no responses against the other cells. These activities were rationalized by molecular docking of the active compounds in BRAFV600E and MEK1 active sites. Moreover, the in-silico pharmacokinetics predictions by Swiss ADME revealed that the active compounds possessed favorable oral bioavailability and drug-likeness properties. [Display omitted] • Three unreported diterpenes were characterized from Euphorbia mauritanica L. • Unreported diterpenes showed significant inhibition of murine melanoma cells. • The active compounds exhibited good affinities toward BRAFV600E and MEK1 kinases. [ABSTRACT FROM AUTHOR]

A serial jatrophane-type diterpenoids, comprised with three undescribed compounds kanesulones C-E (1-3) and four known ones (4-7), were obtained from the roots of Euphorbia kansui. The structures of compounds 1-3 were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS, the absolute configuration of 1 was revealed by single crystal X-ray diffraction. These isolates were assayed for their multidrug resistance reversing activities on human breast adenocarcinoma cell line MCF-7/ADR. Compound 1 possessed potential as low toxic MDR modulator that could promote the efficacy of anticancer drug adriamycin ca. 85-fold at 5 μM, as 12 times stronger than the positive drug verapamil., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Abstract: Four novel (1–4) and one known (5) diterpene polyesters with the jatrophane skeleton were isolated from a methanol extract of the aerial parts of the East Asian weed Euphorbia mongolica Prokh. The isolated compounds were characterized structurally and evaluated for multidrug resistance (MDR) reversing activity on human MDR gene-transfected L5178 mouse lymphoma cells; all these compounds were found to modulate the intracellular drug accumulation. The results highlighted some aspects of the structural requirements of jatrophane diterpenes as MDR modulators. [Copyright &y& Elsevier]

Abstract: Jatrophane diterpenes were shown to be inhibitors of P-glycoprotein (P-gp). There are also evidences on their microtubule-interacting activity in cancer cells. We evaluated new anti-cancer characteristics of two jatrophane type compounds from Euphorbia dendroides. For that purpose, the model system of sensitive non-small cell lung cancer cell line (NCI-H460) and its resistant counterpart (NCI-H460/R) was used. Although both jatrophanes showed inhibitory effect on cancer cell growth, they were non-toxic for peripheral blood mononuclear cells (PBMC). We examined their effects in combination with paclitaxel (PTX), a well-known mitotic spindle interacting chemotherapeutic. Jatrophanes overcome PTX resistance in concentration-dependent manner in MDR cancer cell line (NCI-H460/R). We observed that this synergistic effect is not caused merely by P-gp inhibition. In combination with PTX, jatrophanes induce cell killing and change cell cycle distribution leading to G2/M arrest. Furthermore, they exert an anti-angiogenic effect by decreasing the vascular endothelial growth factor (VEGF) secretion. The reduction of the level of mdr1 mRNA expression in sensitive cells, suggests that these compounds could not contribute to the development of resistance. In conclusion, present study provides a rational basis for the new cancer treatment approach with jatrophanes that are non-toxic to normal cells and have new favorable anti-cancer characteristics. [Copyright &y& Elsevier]

The enantioselective synthesis of the C-14 to C-5 cyclopentane segment of jatrophane diterpenes is reported. An Evans aldol addition, a Horner–Wadsworth–Emmons olefination and a thermal intramolecular carbonyl ene reaction of an α-keto ester served as key C/C-connecting transformations. [Copyright &y& Elsevier]

The reaction mechanism of the intramolecular [2 + 2] cycloaddition from a jatrophane precursor to the gaditanane skeleton, an unprecedented 5/6/4/6-fused tetracyclic ring framework recently isolated from Euphorbia spp., was studied using the bond reactivity indices approach. Furthermore, six diterpenoids, including three undescribed jatrophanes isolated from E. gaditana Coss, were described. The structures of these compounds were deduced by a combination of 2D NMR spectroscopy and ECD data analysis. Image 1 • Three undescribed jatrophanes were isolated from Euphorbia gaditana Coss. • Biosynthesis of gaditanane skeleton was studied by bond reactivity indices approach. • An intramolecular [2 + 2] cycloaddition of a jatrophane gives gaditanane skeleton. [ABSTRACT FROM AUTHOR]

Two new ingenane diterpenoids (1–2), four new jatrophane diterpenoids (3–6), and seven known analogues (7–13), were isolated from the 95% ethanol extract of Euphorbia esula. Their structures were determined by extensive spectroscopic methods and ECD data analysis. These compounds were assayed for their anti-osteoporotic activity in a bone marrow-derived macrophage (BMM) cell line, and compounds 2, 4, 7, 8, 9, and 11 significantly inhibited the formation of osteoclasts with IC 50 values of 3.4, 4.3, 2.1, 0.5, 1.5, and 4.5 μM, respectively. These compounds also dose-dependently reduced the activity of nuclear factor activated T-cell cytoplasmic 1 (NFATc1). This study reveals the anti-osteoporotic effects of ingenane diterpenoids for the first time. Unlabelled Image • Thirteen ingenane- and jatrophane-type diterpenoid were isolated. • Ingenane-type diterpenoid exhibited potent anti-osteoclastogenesis activity. • Compound 8 exhibited most potent anti-osteoclastogenesis activity with IC 50 value of 0.5 μM. [ABSTRACT FROM AUTHOR]

In this study, fourteen ingenane-type and nine jatrophane-type diterpenoids were isolated from Euphorbia kansui , including seven undescribed compounds. Kansuingenol A-C have the 6,7-vicinal diol moiety, and Kansuijatrophanol A and B possess the 11,12-vicinal diol moiety, both of which are rarely reported. 3,4-(Methylenedioxy) cinnamyl moiety was found for the first time in jatrophane-type diterpenoids, as shown in Kansuijatrophanol C and D. The absolute configurations of seven undescribed compounds have been analyzed and assigned by the modified Mosher's method, Mo 2 (OAc) 4 -induced circular dichroism (ICD) method, and CD exciton chirality method. All compounds were screened for their antiproliferative effects against HepG2, MCF-7 and DU145 cell lines. Regarding the HepG2 cells, Kansuijatrophanol C exhibited the most promising inhibition with the IC 50 value of 9.47 ± 0.31 μ M. Regarding the MCF-7 and DU145 cells, Kansuijatrophanol D exhibited the most promising inhibition with the IC 50 values of 6.29 ± 0.18 and 4.19 ± 0.32 μ M, respectively. Image 1 • Senen undescribed diterpenoids and sixteen known compounds were reported. • 3,4-(Methylenedioxy) cinnamyl moiety was found for the first time in jatrophane-type diterpenoids, as shown in 6 and 7. • Absolute configurations have been assigned by three methods based on structural characteristics. • Compounds with vicinal diol and 3,4-(methylenedioxy)cinnamyl moiety have good antiproliferative effects. [ABSTRACT FROM AUTHOR]

The jatrophane class of natural products exhibit a wide range of biological activities with certain members of this family of complex sesquiterpenes being P-glycoprotein inhibitors. Considerable attention has been paid to the synthesis of biologically active jatrophanes although very few have succumbed to total synthesis. Herein we report a synthesis of the cyclopentane core of pepluanin A, a potent P-glycoprotein inhibitor, that features an iodocarbocyclization and an invertive acetal formation as key steps. Image 1 • Synthesis of the core of the P-glycoprotein inhibitor pepluanin A reported. • Key methods involve selective iodocyclization and invertive acetal formation. • Exploration of cylization - lactonization reported. [ABSTRACT FROM AUTHOR]

Macrocyclic diterpenoids produced by plants of the Euphorbiaceae family are of considerable interest due to their high structural diversity; and their therapeutically relevant biological properties. Over the last decade many studies have reported the ability of macrocyclic diterpenoids to inhibit in cellulo the cytopathic effect induced by the chikungunya virus. This review; which covers the years 2011 to 2019; lists all macrocyclic diterpenoids that have been evaluated for their ability to inhibit viral replication. The structure–activity relationships and the probable involvement of protein kinase C in their mechanism of action are also detailed. [ABSTRACT FROM AUTHOR]

Phytochemical investigation of the MeOH extract obtained from the aerial parts of the annual weed Euphorbia exigua L. resulted in the isolation of two novel (1, 2) and one known (3) jatrophane diterpenes. Their structures were established by extensive 1D- and 2D-NMR spectroscopy and HR-ESI-MS. The isolated compounds were evaluated for multidrug resistance (MDR) reversing activity on human MDR gene-transfected L5178 mouse lymphoma cells; and all three compounds were found to modulate the intracellular drug accumulation., (Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.)