Indonesian Euphorbiaceae: Ethnobotanical Survey, In Vitro Antibacterial, Antitumour Screening and Phytochemical Analysis of Euphorbia atoto.

Indonesia is among the countries with the most significant biodiversity globally. Jamu, the traditional medicine of Indonesia, predominantly uses herbal materials and is an integral component of the Indonesian healthcare system. The present study reviewed the ethnobotanical data of seven Indonesian Euphorbiaceae species, namely Euphorbia atoto, E. hypericifolia, Homalanthus giganteus, Macaranga tanarius, Mallotus mollissimus, M. rufidulus, and Shirakiopsis indica, based on the RISTOJA database and other literature sources. An antimicrobial screening of the plant extracts was performed in 15 microorganisms using the disk diffusion and broth microdilution methods, and the antiproliferative effects were examined in drug-sensitive Colo 205 and resistant Colo 320 cells by the MTT assay. The antimicrobial testing showed a high potency of M. tanarius, H. giganteus, M. rufidulus, S. indica, and E. atoto extracts (MIC = 12.5-500 µg/mL) against different bacteria. In the antitumour screening, remarkable activities (IC50 0.23-2.60 µg/mL) were demonstrated for the extracts of H. giganteus, M. rufidulus, S. indica, and E. atoto against Colo 205 cells. The n-hexane extract of E. atoto, with an IC50 value of 0.24 ± 0.06 µg/mL (Colo 205), was subjected to multistep chromatographic separation, and 24-methylene-cycloartan-3ß-ol, jolkinolide E, tetra-tert-butyl-diphenyl ether, α-tocopherol, and ß-sitosterol were isolated.

Anticancer Meroterpenoids from Centrapalus pauciflorus leaves: Chromone- and 2,4-Chromadione-Monoterpene Derivatives.

Eight previously undescribed chromones, named pauciflorins F-M and two 5-methyl-2,4-chromadione derivatives named as pauciflorins N and O, were isolated from the methanol extract of the leaves of Centrapalus pauciflorus (Willd.) H.Rob. together with the known (+)-spiro-ethuliacoumarin. The structures were determined via extensive spectroscopic analyses, including HRESIMS, 1D NMR (1H, 13C JMOD), and 2D NMR (HSQC, HMBC, 1H-1H COSY, and NOESY) experiments. Through an MTT assay, seven isolated compounds were tested for their antiproliferative properties against human adherent breast (MCF-7, MDA-MB-231), cervical (HeLa, SiHa), and ovarian (A2780) cancer cell lines. Pauciflorin F was effective against MCF-7 breast cancer cells, its activity (IC50 5.78 µM) was comparable to that of the reference agent cisplatin (IC50 5.78 µM).

Isolation of compounds from the roots of Ambrosia artemisiifolia and their effects on human cancer cell lines.

Common ragweed (Ambrosia artemisiifolia L.) is an invasive plant in Europe with spreading use in the contemporary folk medicine. The chemical composition of the above-ground parts is extensively studied, however, the metabolites of the roots are less discovered. By multiple chromatographic purification of the root extracts, we isolated thiophene A (1), n-dodecene (2), taraxerol-3-O-acetate (3), α-linoleic acid (4), (+)-pinoresinol (5), and thiophene E (7,10-epithio-7,9-tridecadiene-3,5,11-triyne-1,2-diol) (6). The 1H NMR data published earlier for 1 were supplemented together with the assignment of 13C NMR data. Thiophene E (6), which is reported for the first time from this species, exerted cytotoxic and antiproliferative effects on A-431 epidermoid skin cancer cells, whereas taraxerol-3-O-acetate (3) and α-linoleic acid (4) had slight antiproliferative effect on gynecological cancer cell lines. Thiophene E (6) and taraxerol-3-O-acetate (3) displayed antiproliferative and cytotoxic effects on MRC-5 fibroblast cells. Thiophene E (6) exerted weak antibacterial activity (MIC 25 µg/mL) on MRSA ATCC 43300, on Staphylococcus aureus ATCC 25923, Escherichia coli AG100 and E. coli ATCC 25922 both thiophenes were inactive. Although the isolated compounds exerted no remarkable cytotoxic or antiproliferative activities, the effects on MRC-5 fibroblast cells highlight the necessity of further studies to support the safety of ragweed root.

Pauciflorins A-E, Unexpected Chromone-Monoterpene-Derived Meroterpenoids from Centrapalus pauciflorus.

Five unusual meroterpenoids based on new carbon skeletons, pauciflorins A-E (1-5), were isolated by multistep chromatographic separations of a methanol extract of the aerial parts of Centrapalus pauciflorus. Compounds 1-3 are derived by the connection of a 2-nor-chromone and a monoterpene unit, whereas 4 and 5 are dihydrochromone-monoterpene adducts with a rarely occurring orthoester functionality. The structures were solved using 1D and 2D NMR, HRESIMS, and single-crystal X-ray diffraction. Pauciflorins A-E were evaluated for antiproliferative activity against human gynecological cancer cell lines, but were inactive (IC50 < 10 µM) in each case.

Isolation and NMR Scaling Factors for the Structure Determination of Lobatolide H, a Flexible Sesquiterpene from Neurolaena lobata.

A new flexible germacranolide (1, lobatolide H) was isolated from the aerial parts of Neurolaena lobata. The structure elucidation was performed by classical NMR experiments and DFT NMR calculations. Altogether, 80 theoretical level combinations with existing 13C NMR scaling factors were tested, and the best performing ones were applied on 1. 1H and 13C NMR scaling factors were also developed for two combinations utilizing known exomethylene containing derivatives, and the results were complemented by homonuclear coupling constant (JHH) and TDDFT-ECD calculations to elucidate the stereochemistry of 1. Lobatolide H possessed remarkable antiproliferative activity against human cervical tumor cell lines with different HPV status (SiHa and C33A), induced cell cycle disturbance and exhibited a substantial antimigratory effect in SiHa cells.

Isolation of the Lanostane Triterpenes Pholiols L-S from Pholiota populnea and Evaluation of Their Antiproliferative and Cytotoxic Activities.

Pholiols L-S (1−8), eight undescribed triterpenes were isolated from the sporocarps of the mushroom Pholiota populnea. Various chromatographic techniques, such as open column chromatography, flash chromatography, gel filtration, preparative thin layer chromatography, and HPLC, were applied to purify the compounds. The structure elucidation was carried out by spectroscopic analysis, including 1D (1H NMR and 13C JMOD) and 2D NMR (1H-1H COSY, HSQC, HMBC and NOESY) and HRESIMS experiments. The isolated compounds had lanostane (1−7) or trinorlanostane (8) skeletons; all of them were substituted with 3-hydroxy-3-methylglutaroyl group or its 6-methyl ester. Five compounds (1, 2, 4, 6, and 8) were investigated for their antiproliferative and cytotoxic activity in vitro by MTT assay on breast cancer (MCF-7), human colon adenocarcinoma (sensitive Colo 205, and resistant Colo 320), non-small cell lung cancer (A549), and human embryonic lung fibroblast (MRC-5) cell lines. Pholiols M (2) and O (4) showed antiproliferative activity against the MCF-7 cell line with IC50 of 2.48 and 9.95 µM, respectively. These compounds displayed tumor cell selectivity on MCF-7 cells with SI values of >40 (2) and 4.3 (4), but they did not show a cytotoxic effect, proving their action exclusively on tumor cell proliferation. Pholiols L (1) and Q (8) were found to have selective cytotoxicity on drug resistant cells in comparison to their effects on Colo320 and Colo205 cells [relative resistance values 0.84 (1) and 0.62 (8)].

Ingol, ent-atisane, and stachane-type diterpenoids from Euphorbia deightonii with multidrug resistance reversing activity.

Nine previously undescribed ingol-type diterpenoid polyesters with eighteen known ingol esters, two ent-atisane, and one stachane diterpenoid were isolated from the methanol extract of Euphorbia deightonii Croizat. The structures were established by extensive spectroscopic analysis involving 1D (1H, 13C J-modulation) and 2D NMR experiments, HRESIMS measurements, and the comparison of the spectroscopic data with reported literature values. The cytotoxic concentrations of 13 isolated compounds were determined, and the compounds were investigated for multidrug resistance modulating activity on an L5178 mouse lymphoma cell line using a rhodamin 123 accumulation assay. Six ingol esters demonstrated the significant inhibition of P-glycoprotein, while the two ent-atisane diterpenoids were found to be inactive. The measured activities allowed to establish some structure-activity relationships. Notably, lower and higher-type diterpenoids simultaneously occurred in E. deightonii.

Cytotoxicity, apoptosis inducing activity and Western blot analysis of tanshinone derivatives from Stachys parviflora on prostate and breast cancer cells.

Cytotoxic activities of methanolic crude extract of Stachys parviflora (Lamiaceae family) and its sub-fractions were primarily evaluated against human breast adenocarcinoma (MCF-7 and MDA-MB-231) and prostate (PC3) cell lines. The methanolic extract exhibited the highest activity, and was chosen for the isolation procedure. Four diterpenoid quinones, namely miltirone [1], tanshinone IIA [2], 1-hydroxy-tanshinone IIA [3], and cryptotanshinone [4] were isolated. Notably, this is the first report on the isolation and/or characterization of the mentioned diterpenoids from the Stachys genus. In this study, 1-hydroxy-tanshinone IIA [3] displayed the highest cytotoxicity among the isolated compounds. The mechanism of the cytotoxicity of methanolic extract and isolated compounds was further investigated by the utilization of propidium iodide staining (PI) assay. The results showed that the methanolic extract and 1-hydroxy-tanshinone IIA [3] enhanced DNA fragmentation in PC3 and MCF-7 cells. Moreover, the western blotting analysis demonstrated increasing and decreasing protein levels of Bax and Bcl2, respectively, and cleaved poly ADP-ribose polymerase (PARP). Further bioassay-guided phytochemical assessments of S. parviflora can be suggested as a promising approach for discovering potent bioactive secondary metabolites.

Antimicrobial, Multidrug Resistance Reversal and Biofilm Formation Inhibitory Effect of Origanum majorana Extracts, Essential Oil and Monoterpenes.

Origanum majorana L. is a widely used medicinal plant; its distilled oil and preparations are extensively utilised in the phytotherapy and food industries. The objective of this study is to evaluate the extracts and the essential oil (EO) of Origanum majorana L, and its monoterpenes for antimicrobial, bacterial multidrug resistance reversing, and biofilm formation inhibitory potency. The composition of EO and n-hexane extract was characterized by GC-MS. In the essential oil terpinen-4-ol (24.92%), trans-sabinene hydrate (25.18%), γ-terpinene (6.48%), cis-sabinene hydrate (5.44%), p-cymene (4.72%), sabinene (4.53%), α-terpineol (4.43%), and α-terpinene (3.00%) were found as the main constituents while trans-sabinene hydrate (1.43%), and terpinen-4-ol (0.19%) were detected in the n-hexane extract besides a series of hydrocarbons. The antibacterial activity of EO and terpinen-4-ol, α-terpinene, and linalool was also assessed against sensitive and drug-resistant S. aureus, and E. coli strains with MIC values of 0.125-0.250% and 30-61 µM, respectively. In the efflux pump (EP) inhibitory assay, made by the ethidium bromide accumulation method in E. coli ATCC 25922, and AG100 and S. aureus ATCC 25923, and MRSA ATCC 43300 strains, EO exhibited substantial activity, especially in the E. coli ATCC 25922 strain. Among the EO constituents, only sabinene was an EP inhibitor in sensitive Escherichia strain. In the case of S. aureus strains, EO and sabinene hydrate exhibited moderate potency on the drug-resistant phenotype. The antibiofilm effects of the samples were tested by crystal violet staining at sub-MIC concentration. γ-Terpinene, terpinen-4-ol, sabinene, sabinene hydrate and linalool were found to be effective inhibitors of biofilm formation (inhibition 36-86%) on E. coli ATCC 25922 and S. aureus MRSA ATCC 43300, while EO was ineffective on these strains. In contrast to this, biofilms formed by E. coli AG100 and S. aureus ATCC 25923 were significantly inhibited by the EO; however, it was not affected by any of the monoterpenes. This observation suggests that the antibiofilm effect might be altered by the synergism between the components of the essential oil.

Polyoxypregnane Ester Derivatives and Lignans from Euphorbia gossypina var. coccinea Pax.

From the aerial parts of Euphorbiagossypina var. coccinea Pax., eight new pregnane glycosides (euphogossypins A-H, 1-8) of the cynanforidine and deacetylmetaplexigenin aglycons, two new lignans (gossypilignans A and B, 9 and 10), and four known compounds, namely, the pregnane 12-O-benzoyldeaxcylmetaplexigenin (11), the lignan 9α-hydroxypinoresinol (12), and the flavonoids naringenin (13) and quercitrin (14) were isolated. The structure elucidation of the new compounds was carried out by a spectroscopic analysis, including HRMS, 1D (1H, 13C JMOD), and 2D NMR (HSQC, 1H-1H COSY, HMBC, and NOESY) experiments. The obtained pregnane glycosides were substituted with acetyl and benzoyl ester moieties, and sugar chains containing thevetose, cymarose, digitoxose, and glucose monosaccharides. All of the compounds are described for the first time from E. gossypina var. coccinea. The isolated pregnanes and lignans were tested for their antiproliferative activity on HeLa cells using the MTT assay; the compounds exerted no significant effect against the tumor cells.

Jacaranone Derivatives with Antiproliferative Activity from Crepis pulchra and Relevance of This Group of Plant Metabolites.

Jacaranones are a small group of specific plant metabolites with promising biological activities. The occurrence of jacaranones is limited to only a few plant families, with Asteraceae being the most abundant source of these compounds. Therefore, jacaranones can also serve as chemotaxonomic markers. Our phytochemical investigation of Crepis pulchra L. (Asteraceae) resulted in three jacaranone derivatives (jacaranone, 2,3-dihydro-2-hydroxyjacaranone, 2,3-dihydro-2-methoxyjacaranone), and (6R,9S)-3-oxo-α-ionol-ß-d-glucopyranoside, fulgidic acid, 12,15-octadecadienoic acid methyl ester, scopoletin and apigenin-7-O-ß-d-glucoside. This is the first report on the isolation of jacaranones from a species belonging to the Cichorioideae subfamily of Asteraceae. Jacaranone derivatives were subjected to an in vitro antiproliferative assay against a panel of human cancer cell lines (MCF-7, MDA-MB-231, HeLa, and C33A), revealing high or moderate activities, with IC50 values ranging from 6.3 to 26.5 µM.

Unique Phenanthrenes from Juncus ensifolius and Their Antiproliferative and Synergistic Effects with the Conventional Anticancer Agent Doxorubicin against Human Cancer Cell Lines.

Phenanthrenes are the main special metabolites of Juncaceae species from phytochemical, pharmacological, and chemotaxonomical points of view. The present study focused on the isolation, structure determination, and pharmacological investigation of phenanthrenes from Juncus ensifolius. Nineteen compounds, including 17 phenanthrenes, were identified from the methanol extract of the plant. Thirteen compounds, namely, ensifolins A−M (1−13), were obtained for the first time from natural sources. Four phenanthrenes [2-hydroxy-1,7-dimethyl-5-vinyl-9,10-dihydrophenanthrene (14), juncuenin B (15), juncatrin B (16), and sylvaticin A (17)], 4-hydroxybenzaldehyde (18) and luteolin (19) were isolated for the first time from J. ensifolius. Ensifolins A (1) and B (2) are structurally unique phenanthrenes, considering that they are flavonoid- (1) or benzaldehyde-adducts (2). The antiproliferative activity of all isolated compounds against HeLa, COLO 205, and COLO 320 cancer cells and a non-tumor (MRC-5) cell line was tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability assay. The luteolin-substituted phenanthrene ensifolin A (1) proved to be the most active against all three cancer cell lines (IC50 values 3.9−12.7 µM) and showed good selectivity (SI = 4.95) in the case of COLO 205. The best selectivity was recorded for ensifolins D (4, SI > 5.15, HeLa), H (8, SI > 8.13, HeLa), and 17 (SI > 9.43, HeLa). The synergistic activity of the compounds with doxorubicin was also tested on HeLa cells, and ensifolins E (5) and H (8) exhibited very strong synergism (CI < 0.1). In conclusion, these phenanthrenes are worthy of further investigation.

Triterpenes from Pholiota populnea as Cytotoxic Agents and Chemosensitizers to Overcome Multidrug Resistance of Cancer Cells.

The detailed mycochemical analysis of the n-hexane extract of Pholiota populnea led to the isolation of four new lanostane diesters, named pholiols A-D (1-4), together with an acyclic triterpene, (3S,6E,10E,14E,18E,22S)-2,3,22,23-tetrahydroxy-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene (5), ergosterol (6), and 3ß-hydroxyergosta-7,22-diene (7). The isolation was carried out by multistep flash chromatography, and the structures were elucidated using extensive spectroscopic analyses, including 1D and 2D NMR and MS measurements. The isolated metabolites (1-6) were investigated for cytotoxic activity against Colo205 and Colo320 colon adenocarcinoma and nontumoral MRC-5 cell lines. Among the tested compounds, ergosterol (6) showed substantial cytotoxic activity against all cell lines with IC50 values of 4.9 µM (Colo 205), 6.5 µM (Colo 320), and 0.50 µM (MRC) with no tumor cell selectivity. A P-glycoprotein efflux pump modulatory test on resistant Colo320 cells revealed that pholiols A (1) and B (2) and linear triterpene polyol 5 have the capacity to inhibit the efflux-pump overexpressed in the cells. Moreover, the drug interactions of triterpenes with doxorubicin were studied by the checkerboard method on Colo 320 cells. Pholiols B (2) and D (4) interacted in synergistic and acyclic triterpene 5 in a very strong synergistic manner; the combination index (CI) values at 50% of the growth inhibition dose (ED50) were found to be 0.348, 0.660, and 0.082, respectively. Our results indicate that P. populnea is a promising source for finding new triterpenes with significant chemosensitizing activity on cancer cells.

Isolation, Structure Determination of Sesquiterpenes from Neurolaena lobata and Their Antiproliferative, Cell Cycle Arrest-Inducing and Anti-Invasive Properties against Human Cervical Tumor Cells.

Seven new germacranolides (1-3, 5-8), among them a heterodimer (7), and known germacranolide (4), eudesmane (9) and isodaucane (10) sesquiterpenes were isolated from the aerial parts of Neurolaena lobata. Their structures were determined by using a combination of different spectroscopic methods, including HR-ESIMS and 1D and 2D NMR techniques supported by DFT-NMR calculations. The enantiomeric purity of the new compounds was investigated by chiral HPLC analysis, while their absolute configurations were determined by TDDFT-ECD and OR calculations. Due to the conformationally flexible macrocycles and difficulties in assigning the relative configuration, 13C and 1H NMR chemical shift and ECD and OR calculations were performed on several stereoisomers of two derivatives. The isolated compounds (1-10) were shown to have noteworthy antiproliferative activities against three human cervical tumor cell line with different HPV status (HeLa, SiHa and C33A). Additionally, lobatolide C (6) exhibited substantial antiproliferative properties, antimigratory effect, and it induced cell cycle disturbance in SiHa cells.

Ingol and Ingenol-Type Diterpenes from Euphorbia trigona Miller with Keratinocyte Inhibitory Activity.

Ingenol mebutate, isolated from Euphorbia peplus, is an ingenane-type diterpenoid, primarily used for the topical treatment of actinic keratosis, a premalignant skin condition. The aim of our work was to investigate other Euphorbia species to find structurally similar diterpenes that can be used as alternatives to ingenol mebutate. Pharmacological investigation of Euphorbia candelabrum, Euphorbia cotinifolia, Euphorbia ramipressa, and Euphorbia trigona revealed the potent keratinocyte (HPV-Ker cell line) inhibitory activity of these spurge species. From the methanolic extract of the aerial parts of Euphorbia trigona Miller, the most active species, five ingol (1-5) and four ingenane-type diterpenoids (6-9) were isolated by various chromatographic separation techniques, including open column chromatography, vacuum liquid chromatography, thin-layer chromatography, and high-performance liquid chromatography. The structures of the compounds were determined by NMR spectroscopic analysis and by comparison of the assignations with the literature data. The cytotoxic activity of the compounds against keratinocytes was tested in vitro by using ingenol mebutate as a positive control. Among the isolated compounds, two ingenane derivatives (6 and 7) exhibited remarkably stronger cytotoxic activity (IC50 values 0.39 µM and 0.32 µM, respectively) on keratinocytes than ingenol mebutate (IC50 value 0.84 µM). These compounds could serve as starting materials for further investigations to find alternatives to Picato® (with active substance ingenol mebutate), which was withdrawn from marketing authorization in the European Union.

Triterpenes and Phenolic Compounds from the Fungus Fuscoporia torulosa: Isolation, Structure Determination and Biological Activity.

Investigation of the methanol extract of the poroid fungus Fuscoporia torulosa resulted in the isolation of a novel triterpene, fuscoporic acid (1), together with inoscavin A and its previously undescribed Z isomer (2 and 3), 3,4-dihydroxy-benzaldehide (4), osmundacetone (5), senexdiolic acid (6), natalic acid (7), and ergosta-7,22-diene-3-one (8). The structures of fungal compounds were determined on the basis of NMR and MS spectroscopic analyses, as well as molecular modeling studies. Compounds 1, 6-8 were examined for their antibacterial properties on resistant clinical isolates, and cytotoxic activity on human colon adenocarcinoma cell lines. Compound 8 was effective against Colo 205 (IC50 11.65 ± 1.67 µM), Colo 320 (IC50 8.43 ± 1.1 µM) and MRC-5 (IC50 7.92 ± 1.42 µM) cell lines. Potentially synergistic relationship was investigated between 8 and doxorubicin, which revealed a synergism between the examined compounds with a combination index (CI) at the 50% growth inhibition dose (ED50) of 0.521 ± 0.15. Several compounds (1 and 6-8) were tested for P-glycoprotein modulatory effect in Colo 320 resistant cancer cells, but none of the compounds proved to be effective in this assay. Fungal metabolites 2-5 were evaluated for their antioxidant activity using the oxygen radical absorbance capacity (ORAC) and DPPH assays. Compounds 4 and 5 were found to have a considerable antioxidant effect with EC50 0.25 ± 0.01 (DPPH) and 12.20 ± 0.92 mmol TE/g (ORAC). The current article provides valuable information on both the chemical and pharmacological profiles of Fuscoporia torulosa, paving the way for future studies with this species.

Juncaceae Species as Promising Sources of Phenanthrenes: Antiproliferative Compounds from Juncus maritimus Lam.

Juncaceae family represents an abundant source of phenanthrenes. In continuation of our work aiming at the isolation of biologically active compounds from Juncaceae species, Juncus maritimus Lam. was subjected to phytochemical and pharmacological investigations. The isolation process was carried out by using combined extraction and chromatographic methods. The structures of the obtained chemical compounds were elucidated by spectroscopic analysis, including HRESIMS, 1D (1H, 13C-JMOD), and 2D (1H-1H-COSY, HSQC, HMBC, NOESY) NMR spectra. Four new [maritins A-D (1-4)] and seven known phenanthrenes (5-11) were isolated from the plant, of which two (4 and 11) are phenanthrene dimers composed of effusol monomers. Maritin C (3) has an unusual 4,5-ethanophenanthrene skeleton most likely produced by biosynthetic incorporation of a vinyl group into a cyclohexadiene ring. Compounds 1-11 were tested for their antiproliferative activity on seven human tumor cell lines (HeLa, HTM-26, T-47D, A2780, A2780cis, MCF-7, KCR) and one normal cell line (MRC-5) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The dimeric phenanthrenes showed strong antiproliferative activity against T-47D cells with IC50 values of 9.1 and 6.2 µM, respectively.

4,5-Seco-5,10-friedo-abietane-type diterpenoids with anticancer activity from Salvia atropatana Bunge.

The purpose of this study is cytotoxicity-guided isolation of the petroleum ether fraction from the roots of Salvia atropatana for the first time, which has shown to growth inhibition and apoptosis induction in MCF-7 and PC3 cells. Bioassay-guided isolation method was conducted for finding compounds with highest cytotoxicity. Different extracts were prepared from the roots of Salvia atropatana. All extracts were tested for their cytotoxic activity against three cancer cell lines (PC3, MCF-7, and MDA-MB-231). The most cytotoxic extract was chosen for further isolation by column chromatography and HPLC. The chemical structures were determined by spectroscopic methods including 1D and 2D NMR. From the petroleum ether extract, four abietane-type diterpenoids, including a new abietane-type diterpenoid, named atropatanene (1), together with three known diterpenoids, 7α-acetoxyroyleanone (2), and a mixture of two isomers, saprorthoquinone and aethiopinone (3+4), were isolated. The latter exhibited substantial cytotoxicity with IC50 value of 8.73 µg/ml against PC3 cells and led to an increasing number of cells in the subG1 region and an increase in the amount of Bax and cleavage of PARP protein, indicating apoptotic cell death. Owing to its numerous biological activities, Salvia species could be represented as a natural potential source against several cancer cell lines.

Antiproliferative Phenanthrenes from Juncus tenuis: Isolation and Diversity-Oriented Semisynthetic Modification.

The occurrence of phenanthrenes is limited in nature, with such compounds identified only in some plant families. Phenanthrenes were described to have a wide range of pharmacological activities, and numerous research programs have targeted semisynthetic derivatives of the phenanthrene skeleton. The aims of this study were the phytochemical investigation of Juncus tenuis, focusing on the isolation of phenanthrenes, and the preparation of semisynthetic derivatives of the isolated compounds. From the methanolic extract of J. tenuis, three phenanthrenes (juncusol, effusol, and 2,7-dihydroxy-1,8-dimethyl-5-vinyl-9,10-dihydrophenanthrene) were isolated. Juncusol and effusol were transformed by hypervalent iodine(III) reagent, using a diversity-oriented approach. Four racemic semisynthetic compounds possessing an alkyl-substituted p-quinol ring (1-4) were produced. Isolation and purification of the compounds were carried out by different chromatographic techniques, and their structures were elucidated by means of 1D and 2D NMR, and HRMS spectroscopic methods. The isolated secondary metabolites and their semisynthetic analogues were tested on seven human tumor cell lines (A2780, A2780cis, KCR, MCF-7, HeLa, HTB-26, and T47D) and on one normal cell line (MRC-5), using the MTT assay. The effusol derivative 3, substituted with two methoxy groups, showed promising antiproliferative activity on MCF-7, T47D, and A2780 cell lines with IC50 values of 5.8, 7.0, and 8.6 µM, respectively.

The electrophysiological effect of cannabidiol on hERG current and in guinea-pig and rabbit cardiac preparations.

Cannabis use is associated with cardiovascular adverse effects ranging from arrhythmias to sudden cardiac death. The exact mechanism of action behind these activities is unknown. The aim of our work was to study the effect of cannabidiol (CBD), tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol on cellular cardiac electrophysiological properties including ECG parameters, action potentials, hERG and IKr ion channels in HEK cell line and in rabbit and guinea pig cardiac preparations. CBD increased action potential duration in rabbit and guinea pig right ventricular papillary muscle at lower concentrations (1 µM, 2.5 µM and 5 µM) but did not significantly change it at 10 µM. CBD at high concentration (10 µM) decreased inward late sodium and L-type calcium currents as well. CBD inhibited hERG potassium channels with an IC50 value of 2.07 µM at room temperature and delayed rectifier potassium current with 6.5 µM at 37 °C, respectively. The frequency corrected QT interval (QTc) was significantly lengthened in anaesthetized guinea pig without significantly changing other ECG parameters. Although the IC50 value of CBD was higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that hERG and potassium channel inhibition might have a role in the possible proarrhythmic adverse effects of cannabinoids in situations where metabolism of CBD impaired and/or the repolarization reserve is weakened.