Jatrophane Diterpenoids Research Articles

Novel Jatrophane Diterpenoids from Euphorbia esula Promotes Lipid Clearance by Transcriptional Regulation of PCSK9.

PCSK9 has been recognized as an efficient target for hyperlipidemia and related cardiovascular/cerebrovascular diseases. However, PCSK9 inhibitors in the clinic are all biological products, and no small molecules are available yet. In the current work, we discovered that the crude extract of Euphorbia esula (E. esula) promoted LDL uptake in vitro and then obtained 8 new and 12 known jatrophane diterpenoids by activity-guided isolation. After summarized their structure-activity relationship of PCSK9 inhibition, we selected compound 11 (C11) with potent activity and high abundance to investigate its mechanism and in vivo efficacy. Mechanistically, C11 bound with HNF1α to influence its nuclear distribution and subsequently inhibit PCSK9 transcription, thereby enhancing LDLR and promoting LDL uptake. Moreover, C11 demonstrated obvious lipid-lowering activity in HFD mouse model. In conclusion, we first revealed the novel application of E. esula in the discovery of a lipid-lowering candidate and highlighted the potential of C11 in the treatment of hyperlipidemia.

Two new jatrophane diterpenoids from Euphorbia helioscopia with activity towards autophagic flux

Nine jatrophane diterpenoids were isolated from the whole plant Euphorbia helioscopia, including two new ones, helioscopnins A (1) and B (2). Comprehensive spectroscopic data analysis and ECD calculations elucidated their structures, including absolute configurations. All compounds were evaluated for bioactivity towards autophagic flux by flow cytometry using HM mCherry-GFP-LC3 cells. Compounds 1, 3, 4, 5, 8, and 9 significantly increased autophagic flux.

Diterpenoids with an unusual tricyclo[10.3.0.02,9]pentadecane skeleton from Pedilanthus tithymaloides as multidrug resistance modulators

Three new diterpenoids with an unusual carbon skeleton, pedilanins A-C (1–3), and nine new jatrophane diterpenoids, pedilanins D-L (4–12), along with five known ones (13–17), were isolated from Pedilanthus tithymaloides. Compounds 1–3 characterize an unprecedented tricyclo[10.3.0.02,9]pentadecane skeleton. Compounds 4–8 are rare examples of the jatrophanes bearing a cyclic hemiketal substructure. Their structures were determined by an extensive analysis of HRESIMS, NMR, quantum-chemical calculation, DP4+ probability, and X-ray crystallographic data. In the bioassay, compounds 1–12 dramatically reversed multidrug resistance in cancer cells with the fold-reversals ranging from 17.9 to 396.8 at the noncytotoxic concentration of 10 μM. The mechanism results indicated that compounds 2 and 3 inhibited the P-glycoprotein (Pgp) transporter function, thus reversing the drug resistance.

Offline two-dimensional normal-phase × reversed-phase liquid chromatography coupled with high-resolution mass spectrometry for comprehensive analysis of chemical constituents in Euphorbia kansui

Euphorbia kansui is the dried root of Euphorbia kansui T. N. Liou ex T.P. Wang. Its main chemical components are diterpenoids, triterpenes, and volatile oil. In this study, an offline two-dimensional (2D) normal-phase × reversed-phase liquid chromatography method coupled with quadrupole time-of-flight mass spectrometry was established to comprehensively analyze the chemical constituents in E. kansui. A total of 240 compounds were identified from the E. kansui extract, including 218 diterpenoids (77 known, 141 new), 16 known volatile oils, and six known triterpenes. The relationship between the structural characteristics and tandem mass spectroscopy fragments of diterpenoids was further analyzed. Based on the characteristic fragment ions, 141 new diterpenoids were determined as 118 ingenane diterpenoids and 23 jatrophane diterpenoids. The newly identified diterpenoids may provide lead compounds for drug discovery, improving the medicinal value of E. kansui.

Jatrophane Diterpenoids from Euphorbia peplus Linn. as Activators of Autophagy and Inhibitors of Tau Pathology.

Ten jatrophane diterpenoids were isolated from the whole plant Euphorbia peplus Linn. including seven new ones, named euphjatrophanes A-G (labeled compounds 1, 2, 4-8). Their structures were elucidated with a combination of spectroscopic and single-crystal X-ray crystallography, enabling the identification of compounds 3, 9, and 10 as the previously published euphpepluones G, K, and L, respectively. All compounds were evaluated for their bioactivity with flow cytometry in assays of autophagic flux in HM Cherry-GFP-LC3 (human microglia cells stably expressing the tandem monomeric mCherry-GFP-tagged LC3) cells. Euphpepluone K (9) significantly activated autophagic flux, an effect that was verified with confocal analysis. Moreover, cellular assays showed that euphpepluone K (9) induced autophagy and inhibited Tau pathology.

Cytotoxicity, anti-diabeticity, and phytocomposition investigation of Vietnamese Euphorbia tithymaloides Linn. (Euphorbiaceae).

In this study, the aerial parts of mature Vietnamese Euphorbia tithymaloides plants were put through cytotoxic, anti-diabetic, and phytocompositional evaluations. Specifically, four extracts (petroleum ether (PE), ethyl acetate (EA), methanol (Me), and aqueous (W)) were prepared by maceration at room temperature. All extracts, together with some isolated compounds, were investigated for cytotoxicity against some human normal and cancer cell lines (fibroblasts, HeLa, NCI-H460, HepG2, MCF-7, and Jurkat) using the standardized modified sulforhodamine B (SRB) assay. Additionally, the anti-diabetic activity of extracts and compounds was evaluated via their α-glucosidase inhibitory capacity. The obtained results indicated that Vietnamese E. tithymaloides extracts exhibited moderate cytotoxic activity, among which the PE extract possessed the highest values, on the NCI-H460 cell line. Second, the aqueous extract was revealed to possess very high α-glucosidase inhibitory activity (IC50 = 113.75 ± 14.02 μg ml-1). From the PE extract, three new jatrophane diterpenoids (named tithymal A, tithymal B, and tithymal C) and two known ones were isolated and structurally elucidated using NMR and MS spectroscopies. Noticeably, tithymal A exhibited significantly high inhibitory activity against α-glucosidase (IC50 = 10.71 ± 0.52 μg ml-1). These observations have significantly highlighted the medicinal potential of Vietnamese E. tithymaloides and expanded its scientific fascination.

Euphylonoids A and B, Two Highly Modified Jatrophane Diterpenoids with Potent Lipid-Lowering Activity from Euphorbia hylonoma.

Euphylonoids A (1) and B (2), two highly modified jatrophane diterpenoids, were isolated from Euphorbia hylonoma. 1 represents a new 9(10→18)-abeo-8,12-cyclojatrophane skeleton containing a cage-like 3,8-dioxatricyclo[5.1.2.04,9]decane core, while 2 is a 14(13→20)-abeo-8,12-cyclojatrophane featuring an unusual 17-oxatetracyclo[12.2.1.01,5.09,13]heptadecane framework. Their structural elucidation was completed by spectroscopic, chemical, computational, and single-crystal X-ray diffraction means. 2 significantly inhibited early adipogenesis in 3T3-L1 adipocytes via activating AMP-activated protein kinase signaling.

Jatrophane diterpenoids from Euphorbia microcarpa (prokh.) krylov with multidrug resistance modulating activity

Eight undescribed jatrophane diterpenoids, namely euphomicrophane A-H, together with thirteen known diterpenes were isolated from the whole plant extracts of Euphorbia microcarpa (Prokh.) Krylov. Among them, euphomicrophane C and F were possessed the endo-type core structure that naturally rarely appeared. The structures of the purified undescribed compounds were established by extensive spectroscopic and spectrometric analysis, and the single-crystal X-ray diffraction analysis was used to determine the absolute configuration of euphomicrophane E, elusone A and euphorbesulin G. All the isolates were screened for their reversal abilities on P-glycoprotein-mediated multidrug resistant cancer cell line MCF-7/ADR. Compounds euphomicrophane G-H and 3β,7β,8α,9α,15β-pentaacetoxy-5β-benzoyloxyjatropha-6(17)-11E-dien-14-one were showed potential chemoreversal effect with reversal fold values 18.67, 17.15, and 16.76 at a concentration of 10.0 μM, being equal to or stronger than the positive drug verapamil (16.68).

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.

Three new jatrophane diterpenoids from Euphorbia peplus Linn. with activity towards autophagic flux

Three undescribed jatrophane diterpenoids, named euphpepluones P-R (1–3), were isolated from the whole plant Euphorbia peplus. The structures of these compounds were elucidated by spectroscopic methods. The absolute configuration of 1 was further assigned by X-ray crystallographic analysis. All compounds were evaluated for bioactivity towards autophagic flux by flow cytometry using HM mCherry-GFP-LC3 cells. Compounds 2 and 6 exhibited significant inhibition of autophagic flux.

Jatrophane Diterpenoids with Kv1.3 Ion Channel Inhibitory Effects from Euphorbia helioscopia.

Chemical investigation of bioactive components from the whole plant of Euphorbia helioscopia resulted in the isolation and identification of 17 new jatrophane diterpenoids, namely, heliojatrone D (1) and helioscopids A-P (2-17), along with 11 known analogues (18-28). The structural elucidation of the new diterpenoids was achieved by the comprehensive analysis of HRESIMS, NMR, and X-ray crystallographic data, as well as using electronic circular dichroism. Structurally, heliojatone D (1) is the fourth natural diterpenoid with a rare bicyclo[8.3.0]tridecane skeleton. The inhibitory effect of the isolated diterpenoids against Kv1.3 ion channels was evaluated in a human embryonic kidney 293 cell model transfected with plasmid encoding Kv1.3, resulting in the identification of a series of potent Kv1.3 ion channel inhibitors, with the most active ones (2 and 15) showing IC50 values of 0.9 μM.

Euphoesulatin A prevents osteoclast differentiation and bone loss via inhibiting RANKL-induced ROS production and NF-κB and MAPK signal pathways

Euphoesulatin A (Eup A), a new jatrophane diterpenoid isolated from the Euphorbia esula L. (Euphorbiaceae), was reported to inhibit RANKL-induced osteoclastogenesis. However, the underlying mechanism and the effect in osteoporosis mouse model are still unclear. This study is the first to demonstrate that Eup A inhibits osteoclastogenesis in vitro and in vivo. Mechanistic analysis suggested that Eup A (3, 6, 12 μM) dose-dependently inhibited osteoclastogenesis by down-regulating the activation of NFATc1 and NF-κB and MAPKs signal pathways. Moreover, Eup A (10 mg/kg) significantly prevented bone loss in ovariectomized mice. This work provides in vitro and in vivo evidence that Eup A could be a potential candidate for the development of anti-osteoporosis agents.

Jatrophane diterpenoids as multidrug resistance modulators from Euphorbia sororia

Eight new jatrophane diterpenoids, Euphosorophane F-M (1–8), as well as fourteen known jatrophane diterpenoids (9–22) were separated and purified from the fructus of Euphorbia sororia, and the chemical structures were determined based on extensive spectroscopic analysis, 1D, 2D NMR and HRESIMS data included. Their absolute configurations of compounds 1, 2, 9, and 22 were elucidated by X-ray crystallographic analysis. These jatrophane diterpenoids showed lower cytotoxicity and compounds 3, 4, 11, 12, 13, 14, and 20 revealed promising multidrug resistance (MDR) reversal ability as modulators compared to verapamil (VRP) by MTT assay. The structure–activity relationship (SAR) exhibited that the absence of keto-carbonyl at C-9 and C-14 was essential to MDR reversal activity and the acyloxies substitution at C-5, C-7, C-8, and C-14 also made the activity difference. Euphosorophane I (4) particularly unfold greater potency (EC50 = 1.82 μM) in reversing P-gp-mediated resistance to doxorubicin (DOX). As shown by fluorescence microscopy, 4 promoted intracellular accumulation of rhodamine 123 (Rh123) and DOX in a dose-dependentmanner than VRP. Flow cytometry indicated that 4 inhibitedP-glycoprotein (P-gp) -dependentRh123 efflux in drug-resistant MCF-7/ADR cells. 4 stimulated P-gp-ATPase activity in a concentration-dependent way and inhibited DOX transport activity. Western blot and real-time qPCR results further illustrated that 4 exhibited superior MDR reversal effect in MCF-7/ADR cells attributed to the activation of ATPase rather than the upregulation of P-gp expression and mRNA levels. In addition, 4 bond to the drug-binding site of P-gp predicted by the molecular docking analysis. Collectively, these results indicated that 4 efficiently reversed P-gp-mediated MDR via inhibiting the ABCB1 drug efflux function. 4 with the advantage of low toxicity and efficient could be used as an adjuvanttherapy drug for breast cancer.

Jatrophane Diterpenoids from Euphorbia peplus as Multidrug Resistance Modulators with Inhibitory Effects on the ATR-Chk-1 Pathway.

Twelve undescribed jatrophane diterpenoids, euphpepluones A-L (1-12), together with seven known analogues (13-19), were isolated from the whole plant of Euphorbia peplus, and their structures were elucidated by spectroscopic studies. The absolute configurations of 1 and 4 were assigned by X-ray crystallographic analysis. All isolates were investigated for their inhibitory effects against the ATR-Chk1 pathway using a Western blotting assay. As a result, 1, 2, 5, 8, 10, and 16 were found to suppress the camptothecin (CPT)-induced phosphorylation of Chk1, indicating that these compounds inhibit the activation of the ATR-Chk1 pathway. A preliminary structure-activity relationship (SAR) study of the isolates was conducted. When compound 10 and CPT were combined, apoptosis was induced in A549 cells with PARP cleavage, while there was no apoptotic effect by treatment with CPT or 10 alone. The data obtained indicate that 10 potentiates the chemotherapeutic sensitivity of A549 cells to CPT.

Stereoselective Construction of the Methylcyclopentane Core of Peditithins B-H with Five Continuous Stereocenters.

A stereoselective construction of the methylcyclopentane core (3) of jatrophane diterpenoids peditithins B-H was achieved in 14 steps from commercially available d-(+)-ribono-1,4-lactone (9). The linear 5-ene-heptanal derived from 9 was cyclized to the five-membered ring by an intramolecular carbonyl ene reaction, and five continuous stereocenters on 3 were stereoselectively introduced via a successive substrate-controlled manner, involving diastereoselective 1,4-addition, MoOPH-induced hydroxylation, and stereospecific epoxidation.

Discovery of ingenane and jatrophane diterpenoids from Euphorbia esula as inhibitors of RANKL-induced osteoclastogenesis

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 IC50 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.

Cytotoxic jatrophane diterpenoids from the aerial parts of Euphorbia helioscopia

A phytochemical study of 80% ethanol extract from the aerial parts of Euphorbia helioscopia led to the isolation of three new jatrophane diterpenoids, euphoheliphanes A-C (1–3). Their structures were established on the basis of spectroscopic data (NMR, IR, UV, and MS). The isolated diterpenoids were tested in vitro for cytotoxic potentials against 6 renal cancer cell lines. As a result, compounds 1–3 exhibited some cytotoxic activities against all the tested tumor cell lines with IC50 values less than 50 μM.

DITERPENOIDS PROFILE OF E. PARALIAS AND E. GENICULATE USING UPLC-ESI/MS SPECTROMETRY

Euphorbia species contain series of macrocyclic diterpenoids which present as mono, di and sometimes triesters and were reported to possess several and diverse biological activities. The aim herein was to use the positive ion mode ultraperformance electron spray ionization mass spectroscopy (UPLC-ESI-MS) as an analytical tool for rapid screening and tentative identification of diterpenoids in the methylene chloride fractions of Euphorbia paralias and Euphorbia geniculate. The identification of compounds was based on ESI-MS and ESI-MS/MS fragmentation pattern, in addition to comparison with reported literature. Five classes were determined including tigliane, ingenane, lathyrane, daphnane and jatrophane diterpenoids esters. Each class of the detected diterpenoids obtained its characteristic ESI-MS/MS fragmentation which facilitates its identification. As a result, a total of fifty two diterpenoids were identified and characterized in E. paralias and E. geniculate. All of these compounds are first report in the two plants by this method. The results demonstrated that the used method could be a rapid, effective analytical tool for screening and characterization of diterpenoids in the complex systems of plants extracts.

Jatrophane Diterpenoids from Euphorbia esula as Inhibitors of RANKL-Induced Osteoclastogenesis.

Eighteen new jatrophane diterpenoids, euphoesulatins A-R (1-18), and three known diterpenoids (19-21) were isolated from Euphorbia esula. Compounds 1-7, 14, and 18 represent a rare type of jatrophane-type diterpenoid containing a nicotinoyloxy group. The absolute configuration of 1 was determined by X-ray crystallography. The compounds were assayed for their antiosteoporotic activity in a bone-marrow-derived macrophage cell line, and compounds 1, 8, and 10 significantly inhibited the formation of osteoclasts, with IC50 values of 1.2, 3.5, and 2.3 μM, respectively. These three compounds also dose-dependently reduced the activity of nuclear factor activated T-cell cytoplasmic 1. This study reveals the antiosteoporotic effects of jatrophane diterpenoids for the first time.

Euphoresulanes A-M, structurally diverse jatrophane diterpenoids from Euphorbia esula.

Thirteen new jatrophane diterpenoids, euphoresulanes A-M (1-13), and seven known analogues (14-20) were isolated from the whole plants of Euphorbia esula. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of 1, 6, and 10 were confirmed by single crystal X-ray diffraction. Compounds 1-20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent cancer cell line HepG2/ADR, and 1, 2, 4, 6, and 8 exhibited comparable activity to the positive drugs. Euphoresulane H (8), the most active MDR modulator, could enhance the efficacy of anticancer drug adriamycin to ca. 33 folds at 5μM. The structure-activity relationship (SAR) study revealed that the acyloxy substitution at C-9 is essential to the activity and presence of H-2 was favorable.