Jatrophane Diterpenes Research Articles

Integration of LC-MS, NMR and molecular docking for profiling of bioactive diterpenes from Euphorbia mauritanica L. with in-vitro anti-SARS-CoV-2 activity.

In spite of tremendous efforts exerted in the management of COVID-19, the absence of specific treatments and the prevalence of delayed and long-term complications termed post-COVID syndrome still urged all concerned researchers to develop a potent inhibitor of SARS-Cov-2. The hydromethanolic extracts of different organs of E. mauritanica were in-vitro screened for the anti-SARS-Cov-2 activity. Then, using an integrated strategy of LC-MS/MS, molecular network and NMR, the chemical profile of the active extract has been determined. Docking studies of the identified compounds in the active extract were carried out at different viral targets to in-silico identify the best target for these compounds. The leaves extract showed the best inhibitory effect with IC 50 8.231±0.04 μg/ml. Based on multiplex of LC-MS/MS, molecular network and NMR, the jatrophane diterpenes were tentatively annotated as the main metabolites of the bioactive leaves extract. In silico studies revealed the potentiality of the compounds in the most active extract to 3CLpro where the compound 20 showed the best binding affinity. Further attention should be paid to the isolation of various jatrophane diterpenes from Euphorbia and evaluating their effects toward SARS-Cov-2 and its molecular targets.

Jatrophane diterpenoids with cytotoxic activity from the whole plant of Euphorbia heliosocpia L

Eight undescribed jatrophane diterpenoids, euphohelinoids A–H, along with 11 known analogues were isolated from the whole plant of Euphorbia heliosocpia L. Among them, euphohelinoids A and B contain a rare type of jatrophane diterpenoid skeleton with a 7,8-seco scaffold. To the best of our knowledge, only two such jatrophane diterpenoids have been reported. In addition, euphohelinoids G and H belong to a rare class of jatrophane diterpene possessing a β-hydroxy group at C-11. Structure elucidation of these undescribed diterpenoids was performed by spectroscopic analysis, including NMR, HRESIMS, IR, electronic circular dichroism (ECD) and DP4+ analysis. The cytotoxicity of 17 abundant jatrophane diterpenes was evaluated against HepG2, HeLa, HL-60, and SMMC-7721 cell lines. Seven compounds presented potent cytotoxicity against the four tested cell lines with IC50 values from 8.1 to 29.7 μM. Moreover, preliminary structure-activity relationships for these jatrophane diterpenoids were discussed.

Two new jatrophane diterpenes from the roots of Euphorbia nicaeensis

In the previous study fifteen jatrophane diterpenes were isolated from the Euphorbia nicaeensis latex. Fourteen of them have been shown to be potent P-glycoprotein (P-gp) inhibitor in two MDR cancer cells (NCI-H460/R and DLD1-TxR). The aim of this study was to determine whether and which jatrophane diterpenes can be isolated from the root of the plant, and then to examine their inhibition power on P-glycoprotein of selected cancer cell lines (NCI- -H460, DLD1, U87, NCI-H460/R, DLD1-TxR and U87-TxR). Two previously undescribed jatrophane diterpenes were isolated from the root of E. nicaeensis collected in Deliblato Sand (Serbia). The structures of the isolated compounds were determined using 1D and 2D NMR, as well as HRESIMS data. The results obtained by MTT assay showed different antitumor potential of these two jatrophanes. Compound 1 inhibited cell growth of non-small cell lung carcinoma cell lines NCI-H460 and NCI-H460/R, as well as glioblastoma cell lines U87 and U87-TxR, while jatrophane 2 was almost completely inactive in the suppression of cancer cell growth in a given range of concentrations. The obtained results also showed that the isolated compounds have an inhibitory effect on P-glycoprotein, as well as that their inhibitory potential is similar.

Diterpenoids with an unprecedented ring system from Euphorbia peplus and their activities in the lysosomal-autophagy pathway.

Three novel jatrophane diterpenes, cyclojatrophanes A-C (1-3), were isolated from the seeds of Euphorbia peplus. Compounds 1-3 featured an unprecedented 5/5/5/11 tetracyclic ring system incorporating ditetrahydropyran rings. Their structures including their absolute configurations were established by extensive spectroscopic analysis, X-ray crystallographic experiments and chemical transformations. In addition, these compounds could significantly activate the lysosomal-autophagy pathway.

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

Diterpene compounds specially macrocyclic ones comprising jatrophane, lathyrane, terracinolide, ingenane, pepluane, paraliane, and segetane skeletons occurring in plants of the Euphorbiaceae family are of considerable interest in the context of natural product drug discovery programs. They possess diverse complex skeletons and a broad spectrum of therapeutically relevant biological activities including anti-inflammatory, anti-chikungunya virus, anti-HIV, cytotoxic, and multidrug resistance-reversing activities as well as curative effects on thrombotic diseases. Among macrocyclic diterpenes of Euphorbia, the discovery of jatrophane and modified jatrophane diterpenes with a wide range of structurally unique polyoxygenated polycyclic derivatives and as a new class of powerful inhibitors of P-glycoprotein has opened new frontiers for research studies on this genus. In this review, an attempt has been made to give in-depth coverage of the articles on the naturally occurring jatrophanes and rearranged jatrophane-type diterpenes isolated from species belonging to the Euphorbiaceae family published from 1984 to March 2019, with emphasis on the biogenesis, isolation methods, structure, biological activity, and structure–activity relationship. Electronic supplementary materialThe online version of this article (10.1007/s11101-020-09667-8) contains supplementary material, which is available to authorized users.

Macrocyclic Diterpenoids from Euphorbia helioscopia and Their Potential Anti-inflammatory Activity.

Guided by 1H NMR spectroscopic experiments using the aromatic protons as probes, 11 macrocyclic diterpenes (1-11) were isolated from the aerial parts of Euphorbia helioscopia. Their full three-dimensional structures, including absolute configurations, were established unambiguously by spectroscopic analysis and single-crystal X-ray crystallographic experiments. Among the isolated compounds, compound 1 is the third member thus far of a rare class of Euphorbia diterpenes featuring an unusual 5/10 fused ring system, and 2-4 are new jatrophane diterpenes. Based on the NMR data of the jatrophane diterpenes obtained in this study as well as those with crystallographic structures reported in the literature, the correlations of the chemical shifts of the relevant carbons and the configurations of C-2, C-13, and C-14 of their flexible macrocyclic ring were considered. Moreover, the anti-inflammatory activities of 1-11 were investigated by monitoring their inhibitory effects on nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells. Compound 1 showed an IC50 of 7.4 ± 0.6 μM, which might be related to the regulation of the NF-κB signaling pathway by suppressing the translocation of the p65 subunit and the consequent reduction of IL-6 and TNF-α secretions.

Bioactive Segetane, Ingenane, and Jatrophane Diterpenes from Euphorbia taurinensis.

A novel segetane (1: ) and jatrophane diterpene (2: ), together with five known diterpenoids possessing segetane (3: ), jatrophane (4: ), and ingenane skeletons (5 - 7: ), were isolated from the methanol extract of Euphorbia taurinensis All. The structure elucidation of the compounds was performed by means of extensive spectroscopic analysis, including HRESIMS and 1D (1H, J-modulated spin-echo carbon experiment) and 2D (HSQC, HMBC, COSY, NOESY) NMR experiments. The multidrug resistance reversing and cytotoxic effects of five diterpenes (1, 4: - 7: ) were studied on the L5178 mouse lymphoma cell line using rhodamine 123 accumulation and the MTT cell viability assay. Segetane and jatrophane diterpenes had no cytotoxic activity on the sensitive parent and multidrug resistance cells, while ingenane diterpenes showed a cytotoxic effect on both cell lines. Ingenanes 6: and 7: and segetane 1: demonstrated the remarkable multidrug resistance modulating effect at 20 µM.

Jatrophane diterpenes from Euphorbia guyoniana are new potent inhibitors of atrial GIRK channels

Two new jatrophane diterpenes, guyonianin G (1) and H (2), were isolated from the methanol extract of Euphorbia guyoniana Boiss. & Reut. The structures were established by means of a combined spectroscopic data analysis, including HRESIMS, and 1D- and 2D-NMR techniques. The isolated compounds were not identical with the previously reported compounds of E. guyoniana, indicating the high chemical diversity of this species. Electrophysiological effects of guyonianin G (1) and H (2), together with four jatrophane diterpenes previously isolated from Euphorbia mongolica, Euphorbia serrulata and Euphorbia salicifolia were investigated on stable transfected HEK–GIRK1/4 (Kir3.4) cell lines using automated patch clamp equipment. Significant blocking activity on GIRK channel was exerted by diterpenes 1–5, but no blocking activity of 6 was detected. The common jatropha-6(17),11E-diene, guyonianin G (1) with three large ester groups (one benzoyl and two isobutanoyl groups) was the most active (70% at 10 μM) GIRK channel inhibitory compound.

Jatrophane diterpenes and cancer multidrug resistance – ABCB1 efflux modulation and selective cell death induction

BackgroundModulation 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. MethodsCompounds 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. ResultsThe 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. ConclusionsThis 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.

Isolation and structure determination of novel jatrophane diterpenes from Euphorbia dulcis and their GIRK-channel-inhibitory activity

GIRK channels (G protein-activated inwardly-rectifying potassium channels) play an important role in the regulation of action potentials in the heart. These membrane proteines are selectively expressed in the atria. Under physiological circumstances GIRK channels facilitate the hyperpolarization and prolong the refractory phase in the myocytes, thus decrease the heart rate. The malfunctions of GIRK channels are considered to be involved in the development of atrial fibrillation (AF). Selective blockade of GIRK channels may offer an alternative way in the treatment of AF [1].

Diterpene Constituents of Euphorbia exigua L. and Multidrug Resistance Reversing Activity of the Isolated Diterpenes.

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.

Cyparissins A and B, jatrophane diterpenes from Euphorbia cyparissias as Pgp inhibitors and cytotoxic agents against ovarian cancer cell lines

From the whole plant of Euphorbia cyparissias, two new diterpenes based on jatrophane skeleton, named cyparissins A and B (1 and 2) were isolated. Their chemical structures were established through a combination of nuclear magnetic resonance spectroscopy and mass spectrometric methods. The new cyparissins A and B were tested to evaluate their ability to inhibit P-glycoprotein-mediated multidrug resistance and their cytotoxic activity against A2780 human ovarian cancer cells, both WT and ADR. Compounds 1 and 2 showed moderate inhibitory effects on P-glycoprotein while showing a significant concentration-depending cytotoxic activity for both cancer cell lines. These isolated compounds are based on a new chemical structure that expands the knowledge base for this class of bioactive metabolites.

New jatrophane diterpenes from Euphorbia osyridea with proapoptotic effects on ovarian cancer cells

A dichloromethane–acetone extract of Euphorbia osyridea Bioss. (Syn. Euphorbia lateriflora Schumach. & Thonn), a spurge endemic to Iran and West Africa, afforded three new jatrophane diterpenes belonging to the 2,3,5,7,8,9,14,15-octahydroxy-jatropha-6(17),11E-diene class along with three known triterpenes. Structures of these compounds were elucidated by spectroscopic methods, especially 2D NMR analyses. Biological effects of these compounds were analyzed by performing MTT and annexin V-FITC and PI staining assays against different cancer cell lines. Results showed that 2,3,5,7,8,9,14,15-octahydroxy-jatropha-6(17), 11E-diene derivatives (1–3) inhibit the cell proliferation through apoptosis in the Caov-4 and OVCAR-3 cancer cell lines.

Progress in the Preparation of Jatrophane Diterpenes

AbstractThe Euphorbiaceae family of plants is one of the largest in the plant kingdom and over the last few decades a vast number of structurally complex and compelling terpenoid natural products have been isolated from the milky latices of Euphorbiaceae species. This review provides a brief overview of the biosynthetic routes leading to Euphorbiaceae diterpenes and outlines their pronounced biological properties. Synthetic approaches to jatrophane diterpenes, an important class of Euphorbiaceae diterpenes, are discussed in detail.

Jatrophanes from Euphorbia squamosa as potent inhibitors of Candida albicans multidrug transporters.

A series of structurally related jatrophane diterpenoids (1-6), including the new euphosquamosins A-C (4-6), was purified from the Iranian spurge Euphorbia squamosa and evaluated for its capacity to inhibit drug efflux by multidrug transporters of Candida albicans. Three of these compounds showed an interesting profile of activity. In particular, deacetylserrulatin B (2) and euphosquamosin C (6) strongly inhibited the drug-efflux activity of the primary ABC-transporter CaCdr1p, an effect that translated, in a yeast strain overexpressing this transporter, into an increased sensitivity to fluconazole. These compounds were transported by CaCdr1p, as shown by the observation of an 11-14-fold cross-resistance of yeast growth, and could also inhibit the secondary MFS-transporter CaMdr1p. In contrast, euphosquamosin A (4) was selective for CaCdr1p, possibly as a result of a different binding mode. Taken together, these observations suggest jatrophane diterpenes to be a new class of potent inhibitors of multidrug transporters critical for drug resistance in pathogenic yeasts.

Synthetic studies directed toward the total synthesis of a jatrophane diterpene

Jatrophane diterpenes are of significant biological importance as they have shown a remarkable potential as a Pgp inhibitor. These diterpenes have a characteristic framework. Synthesis of an advanced synthon was achieved in high yielding steps. The methyl group at C13 was installed using a zinc mediated crotylation. An alkoxy mediated hydrozirconation–iodination on propargylic alcohol to provide vinyl iodide was the highlight of the synthesis of the left hand fragment.

Jatrophane diterpenes as inhibitors of chikungunya virus replication: structure-activity relationship and discovery of a potent lead.

Bioassay-guided purification of an EtOAc extract of the whole plant of Euphorbia amygdaloides ssp. semiperfoliata using a chikungunya virus-cell-based assay led to the isolation of six new (1-4, 9, and 10) and six known (5-7, 8, 11, and 12) jatrophane esters. Their planar structures and relative configurations were determined by extensive spectroscopic analysis, and their absolute configurations by X-ray analysis. These compounds were investigated for selective antiviral activity against chikungunya virus (CHIKV), Semliki Forest virus, Sindbis virus, and HIV-1 and HIV-2 viruses. Compound 3 was found to be the most potent and selective inhibitor of the replication of CHIKV and of HIV-1 and HIV-2 (EC50 = 0.76, IC50 = 0.34 and 0.043 μM, respectively). A preliminary structure-activity relationship study demonstrated that potency and selectivity are very sensitive to the substitution pattern on the jatrophane skeleton. Although replication strategies of CHIK and HIV viruses are quite different, the mechanism of action by which these compounds act may involve a similar target for both viruses. The present results provide additional support for a previous hypothesis that the anti-CHIKV activity could involve a PKC-dependent mechanism.

ChemInform Abstract: Enyne Metathesis Approach Towards the Cyclopentane Motif of Jatrophane Diterpenes.

AbstractThe synthesis of the cyclopentane subunit (IV) of jatrophane diterpenes is described using Grubbs′ enyne metathesis of alkyne (I) and stereoselective Pd‐catalyzed ring opening of the epoxide (III) as key steps.

Diterpenes inhibiting NO production from Euphorbia helioscopia

Three new jatrophane diterpenes (1–3), an unreported spectroscopic data jatrophane diterpenene (4), and nine known analogues (5–13) have been isolated from the whole plants of Euphorbia helioscopia. Their structures were established by detailed spectroscopic data analyses (IR, ESIMS, HR-ESIMS, and 1D and 2D NMR), and the structure of 1 was confirmed by X-ray crystallography. The diterpenes showed inhibitory activities on LPS-induced NO production in murine microglial BV-2 cells.

ChemInform Abstract: Synthesis of an Advanced Intermediate (I) of the Jatrophane Diterpene PI‐4 (II): A Dibromide Coupling Approach.

ChemInformVolume 45, Issue 6 Natural Products ChemInform Abstract: Synthesis of an Advanced Intermediate (I) of the Jatrophane Diterpene PI-4 (II): A Dibromide Coupling Approach. Rita Fuerst, Rita Fuerst Inst. Org. Chem., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorUwe Rinner, Uwe Rinner Inst. Org. Chem., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this author Rita Fuerst, Rita Fuerst Inst. Org. Chem., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorUwe Rinner, Uwe Rinner Inst. Org. Chem., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this author First published: 23 January 2014 https://doi.org/10.1002/chin.201406211Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume45, Issue6February 11, 2014 RelatedInformation