Dimeric 9,10-dihydrophenanthrene derivatives from Bletilla striata and their atropisomeric nature.

Four pairs of undescribed racemic bi(9,10-dihydro) phenanthrene and phenanthrene/bibenzyl atropisomers, bletistriatins A-D (1-4), along with 22 known compounds were isolated from the rhizomes of Bletilla striata. These dimeric derivatives were constructed through direct C-C connection or an oxygen bridge. The structures of new compounds were fully established by extensive analysis of MS, and 1D and 2D NMR spectroscopic data. Owing to sterically hindered rotation around the biaryl axis, these dimeric 9,10-dihydrophenanthrene derivatives can exist as a pair of enantiomers, but were isolated as racemates. Their racemates were separated to yield enantiomerically pure compounds by HPLC on an optically active stationary phase, and were stereochemically characterized on-line by circular dichroism (CD) spectroscopy (LC-CD coupling). Some isolates were evaluated for cytotoxicity against human cancer cell lines HL-60 and A549. Compounds 13, 17, and 20 showed cytotoxicity against HL-60 and A-549 cell lines with IC50 values ranging from 2.56 to 8.67 µM.

Cryptotanshinone possesses therapeutic effects on ischaemic stroke through regulating STAT5 in a rat model.

CONTEXT: Cryptotanshinone (CT), a lipophilic compound extracted from roots of Salvia miltiorrhiza Bunge (Lamiaceae) (Danshen), has multiple properties in diseases, such as pulmonary fibrosis, lung cancer, and osteoarthritis. Our previous findings suggest that CT plays a protective role in cerebral stroke. However, the molecular mechanisms underlying CT protection in ischaemic stroke remain unclear. OBJECTIVE: This study examines the effect of CT on ischaemic stroke. MATERIALS AND METHODS: We used the middle cerebral artery occlusion (MCAO) rat (Sprague-Dawley rats, 200 ± 20 g, n = 5) model with a sham operation group was treated as negative control. MCAO rats were treated with 15 mg/kg CT using intragastric administration. Moreover, TGF-ß (5 ng/mL) was used to treat MCAO rats as a positive control group. RESULTS: The 50% inhibitory concentration (IC50) of CT on CD4+ cell damage was 485.1 µg/mL, and median effective concentration (EC50) was 485.1 µg/mL. CT attenuates the infarct region in the MCAO model. The percentage of CD4+CD25+FOXP3+ Treg cells in the peripheral blood of the MCAO group was increased with CT treatment. The protein level of FOXP3 and the phosphorylation of STAT5 were recovered in the CD4+CD25+ Treg cells of model group after treated with CT. Importantly, the effects of CT treatment were blocked by treatment with the inhibitor STAT5-IN-1 in CD4+ T cells of the MCAO model. DISCUSSION AND CONCLUSION: Our findings not only enhance the understanding of the mechanisms underlying CT treatment, but also indicate its potential value as a promising agent in the treatment of ischaemic stroke. Further study will be valuable to examine the effects of CT on patients with ischaemic stroke.

Four new phenanthrene derivatives from Bulbophyllum retusiusculum.

Three new dihydrophenanthrenes, retusiusine D (1), retusiusine E (2), retusiusine F (3), and a new phenanthrene retusiusine G (4), together with two known dihydrophenanthrenes 4,7-dihydroxy-2,3-methylenedioxy-9,10-dihydrophenanthrene (5) and epemeranthol-A (6) were isolated from the tubers of Bulbophyllum retusiusculum. Their structures were established on the basis of extensive spectroscopic analyses. Compounds 1 and 2 exhibited potent cytotoxic activities against SMMC-7721 and weak cytotoxic activities against HL-60. Compound 4 showed moderate cytotoxic activity against SMMC-7721 and MCF-7.

Dehydroeffusol Pprevents Amyloid ß1-42-mediated Hippocampal Neurodegeneration via Reducing Intracellular Zn2+ Toxicity.

Dehydroeffusol, a phenanthrene isolated from Juncus effusus, is a Chinese medicine. To explore an efficacy of dehydroeffusol administration for prevention and cure of Alzheimer's disease, here we examined the effect of dehydroeffusol on amyloid ß1-42 (Aß1-42)-mediated hippocampal neurodegeneration. Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aß1-42 was injected intracerebroventricularly followed by oral administration for 12 days. Neurodegeneration in the dentate granule cell layer, which was determined 2 weeks after Aß1-42 injection, was rescued by dehydroeffusol administration. Aß staining (uptake) was not reduced in the dentate granule cell layer by pre-administration of dehydroeffusol for 6 days, while increase in intracellular Zn2+ induced with Aß1-42 was reduced, suggesting that pre-administration of dehydroeffusol prior to Aß1-42 injection is effective for Aß1-42-mediated neurodegeneration that was linked with intracellular Zn2+ toxicity. As a matter of fact, pre-administration of dehydroeffusol rescued Aß1-42-mediated neurodegeneration. Interestingly, pre-administration of dehydroeffusol increased synthesis of metallothioneins, intracellular Zn2+-binding proteins, in the dentate granule cell layer, which can capture Zn2+ from Zn-Aß1-42 complexes. The present study indicates that pre-administration of dehydroeffusol protects Aß1-42-mediated neurodegeneration in the hippocampus by reducing intracellular Zn2+ toxicity, which is linked with induced synthesis of metallothioneins. Dehydroeffusol, a novel inducer of metallothioneins, may protect Aß1-42-induced pathogenesis in Alzheimer's disease.

Triptolide: reflections on two decades of research and prospects for the future.

Covering: 2000 to 2020 Triptolide is a bioactive diterpene triepoxide isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal plant whose extracts have been used as anti-inflammatory and immunosuppressive remedies for centuries. Although triptolide and its analogs exhibit potent bioactivities against various cancers, and inflammatory and autoimmune diseases, none of them has been approved to be used in the clinic. This review highlights advances in material sourcing, molecular mechanisms, clinical progress and new drug design strategies for triptolide over the past two decades, along with some prospects for the future course of development of triptolide.

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.

New Fluorene Derivatives from Dendrobium gibsonii and Their α-Glucosidase Inhibitory Activity.

Two new compounds, dihydrodengibsinin (1) and dendrogibsol (2), were isolated from the whole plant of Dendrobium gibsonii, together with seven known compounds (3-9). The structures of the new compounds were elucidated by their spectroscopic data. All these isolates were evaluated for their α-glucosidase inhibitory activities. Dendrogibsol (2) and lusianthridin (7) showed strong α-glucosidase inhibitory activity when compared with acarbose. An enzyme kinetic study revealed that dendrogibsol (2) is a noncompetitive inhibitor of α-glucosidase.

Triptolide Inhibits the Proliferation of HaCaT Cells Induced by IL22 via Upregulating miR-181b-5p.

BACKGROUND: Evidence has been shown that triptolide was effective in the treatment of psoriasis; however, the mechanisms remain poorly understood. Thus, this study aimed to investigate the role of triptolide on the proliferation and differentiation of HaCaT cells which are treated with IL22 to mimic abnormal proliferation/differentiation in keratinocyte of psoriasis. MATERIALS AND METHODS: HaCaT cells were transfected with miR-181b-5p antagomir for 24 h, and then exposed to 10 µM Triptolide for 24 h, following by 100 ng/mL of IL22 for 24 h. In addition, the proliferation and cell cycle distribution in HaCaT cells were assessed by immunofluorescence or flow cytometry assays, respectively. RESULTS: Triptolide obviously upregulated the level of miR-181b-5p in HaCaT cells. In addition, triptolide significantly inhibited IL22-induced proliferation of HaCaT cells via inducing cell cycle arrest. Moreover, IL22 markedly inhibited the differentiation of HaCaT cells, and this phenomenon was reversed by triptolide treatment. In contrast, the effects of triptolide on the proliferation and differentiation in IL22-stimulated HaCaT cells were notably reversed by miR-181b-5p antagomir. Moreover, dual-luciferase assay showed that E2F5 was the direct target of miR-181b-5p in HaCaT cells. Meanwhile, upregulation of miR-181b-5p obviously decreased the level of E2F5 in HaCaT cells. CONCLUSION: In this study, we found that triptolide could inhibit the proliferation and promote the differentiation in IL22-stimulated keratinocytes via upregulating miR-181b-5p. These data indicated that triptolide may be a potential agent for the treatment of psoriasis.

Circadian clock regulates hepatotoxicity of Tripterygium wilfordii through modulation of metabolism.

OBJECTIVES: We aimed to determine the diurnal rhythm of Tripterygium wilfordii (TW) hepatotoxicity and to investigate a potential role of metabolism and pharmacokinetics in generating chronotoxicity. METHODS: Hepatotoxicity was determined based on assessment of liver injury after dosing mice with TW at different circadian time points. Circadian clock control of metabolism, pharmacokinetics and hepatotoxicity was investigated using Clock-deficient (Clock-/- ) mice. KEY FINDINGS: Hepatotoxicity of TW displayed a significant circadian rhythm (the highest level of toxicity was observed at ZT2 and the lowest level at ZT14). Pharmacokinetic experiments showed that oral gavage of TW at ZT2 generated higher plasma concentrations (and systemic exposure) of triptolide (a toxic constituent) compared with ZT14 dosing. This was accompanied by reduced formation of triptolide metabolites at ZT2. Loss of Clock gene sensitized mice to TW-induced hepatotoxicity and abolished the time-dependency of toxicity that was well correlated with altered metabolism and pharmacokinetics of triptolide. Loss of Clock gene also decreased Cyp3a11 expression in mouse liver and blunted its diurnal rhythm. CONCLUSIONS: Tripterygium wilfordii chronotoxicity was associated with diurnal variations in triptolide pharmacokinetics and circadian expression of hepatic Cyp3a11 regulated by circadian clock. Our findings may have implications for improving TW treatment outcome with a chronotherapeutic approach.

Anti-Inflammatory and Cytotoxic Potential of New Phenanthrenoids from Luzula Sylvatica.

Phenanthrenoids have been widely described, in the Juncaceae family, for theirbiological properties such as antitumor, anxiolytic, anti-microbial, spasmolytic, and antiinflammatoryactivities. The Juncaceae family is known to contain a large variety ofphenanthrenoids possessing especially anti-inflammatory and cytotoxic properties. Luzulasylvatica, a Juncaceae species, is widely present in the Auvergne region of France, but has neverbeen studied neither for its phytochemical profile nor for its biological properties. We investigatedthe phytochemical profile and evaluated the potential anti-inflammatory activities of L. sylvaticaaerial parts extracts. A bioassay-guided fractionation was carried out to identify the most activefractions. Nine compounds were isolated, one coumarin 1 and eight phenanthrene derivatives (2-9), including four new compounds (4, 5, 8 and 9), from n-hexane and CH2Cl2, fractions. Theirstructures were established by HRESIMS, 1D and 2D NMR experiments. The biological properties,especially the anti-inflammatory/antioxidant activities (ROS production) and antiproliferativeactivity on THP-1, a monocytic leukemia cell line, of each compound, were evaluated. Threephenanthrene derivatives 4, 6, and 7 showed very promising antiproliferative activities.Phenanthrene derivatives.

Dihydrophenanthrofurans and bisbibenzyl derivatives from the stems of Dendrobium nobile.

Two new dihydrophenanthrofurans (1 and 2) and two new bisbibenzyl derivatives (3 and 4) were isolated from the traditional Chinese medicinal plant Dendrobium nobile, along with four known compounds (5-8). The absolute configurations of compounds 1 and 4 were elucidated through extensive NMR and ECD spectroscopic analyses. New compounds showed no antimicrobial activity against four gram-positive bacterial strains and four gram-negative bacteria at the concentration of 1 mg/mL, but displayed significant cytotoxic activity against HepG2 human hepatic cell line with the IC50 values ranging from 1.25 µM to 19.47 µM.

Aporphine and phenanthrene alkaloids with antioxidant activity from the roots of Stephania tetrandra.

Five new alkaloids (1-5), including three new aporphine alkaloids and two new phenanthrene alkaloids, together with 10 known compounds (6-15) were obtained from the roots of Stephania tetrandra. Their structures were elucidated by spectroscopic methods, single-crystal X-ray diffraction, and electronic circular dichroism analyses. Compounds 7-10, and 13 showed antioxidant activities with malondialdehyde (MDA) inhibitory rates of 62.50 ± 1.91 to 98.44 ± 0.34% at the concentration of 10 µM.

New bisbibenzyl and phenanthrene derivatives from Dendrobium scabrilingue and their α-glucosidase inhibitory activity.

Phytochemical investigation of the whole plant of Dendrobium scabrilingue resulted in the isolation of two new compounds namely dendroscabrols A (1) and B (2), along with eight known compounds (3-10). The structures of these compounds were determined by NMR and HR-ESI-MS experiments. All of the isolates were evaluated for their α-glucosidase inhibitory effect. Dendroscabrol B (2) and RF-3192C (10) showed the most potent α-glucosidase inhibitory activity. Dendroscabrol A (1), gigantol (5), coelonin (7) and lusianthridin (9) also exhibited strong activity as compared with the positive control acarbose.

A new phenanthropyran and a new biphenanthrene from the rhizomes of Dioscorea septemloba and their antioxidant activities.

A new phenanthropyran, dioscorone B (1), and a new phenanthrene (2), together with seven known compounds (3-9), were isolated from the 75% ethanol extract of Dioscorea septemloba rhizomes. The chemical structures of these compounds were elucidated by comprehensive spectroscopic methods including NMR, HRESIMS, IR, and UV spectra. Compounds 1-5 were first isolated from genus Dioscorea. The proton and carbon chemical shifts of compounds 1-9 were unambiguously assigned based on the 1D-NMR and 2D-NMR data. Compounds 1-5 and 8-9 were first tested for their antioxidant activities. Compounds 1 and 2 showed excellent activities with IC50 values of 0.07 ± 0.10 µM and 0.13 ± 0.09 µM, respectively.

Nudol, a phenanthrene derivative from Dendrobium nobile, induces cell cycle arrest and apoptosis and inhibits migration in osteosarcoma cells.

Purpose: Osteosarcoma is the most common malignancy of the bone in children and adolescents. There is an urgent need for the development of novel drugs to treat it. Nudol(1), a phenanthrene compound from the traditional Chinese medicine, Dendrobium nobile, exhibited antiproliferative activity against osteosarcoma cells. Therefore, the aim of the present study was to investigate the role and underlying mechanism of nudol(1) as potential chemotherapy for osteosarcoma. Methods: Cell viability was determined by MTT assay. Cell-cycle phase distribution was analyzed by flow cytometry and Western blot. DAPI staining was used for morphology observation. Apoptosis was analysis via flow cytometry. The expression levels of mRNA and protein related to capase-mediated apoptotic pathway were detected by real-time PCR and western blotting. Migration was determined by wound healing assays. Results: Nudol(1) significantly decreased cell viability in several cancer cell lines. Moreover, nudol(1) caused cell cycle arrest at G2/M phase in U2OS cells, and it also induced cell apoptosis through the caspase-dependent pathway. In addition, treatment with nudol(1) suppressed the migration of U2OS cells. Conclusion: The present study, for the first time, demonstrated effects of nudol(1) on OS in vitro and the potential molecular mechanisms. Accordingly, nudol(1) might have the potential for further development as a lead compound against bone tumor.

Atropisomeric bi(9,10-dihydro)phenanthrene and phenanthrene/bibenzyl dimers with cytotoxic activity from the pseudobulbs of Pleione bulbocodioides.

Bulbocodioidins E-H (1-4), four pairs of undescribed racemic bi(9,10-dihydro)phenanthrene and phenanthrene/bibenzyl atropisomers, along with four known compounds (5-8) were isolated from the ethanol extract of the pseudobulbs of Pleione bulbocodioides. Their structures were established by HRESIMS and comprehensive NMR spectroscopic data analysis. Their absolute configurations were elucidated by comparison of their experimental and calculated ECD (electronic circular dichroism) curves. Furthermore, compound 4a displayed cytotoxic activity against colon cancer (HCT-116), liver cancer (HepG2), and breast cancer (MCF-7) cell lines with IC50 values of 7.6, 3.8 and 3.4 µM, respectively. Compound 6 showed cytotoxic activity against breast cancer cell lines (MCF-7) with IC50 value of 5.4 µM.

Bioactivity-Guided Isolation of Cytotoxic Phenanthrenes from Spiranthes sinensis.

Bioactivity-guided separation led to the isolation of six novel phenanthrenes, spiranthesphenanthrenes A-F (1-6), together with 19 known compounds, including seven phenanthrenes (7-13), one bibenzyl compound (14), five flavonoids (15-16 and 20-22), and six simple phenolic compounds (17-19 and 23-25), from the petroleum ether (PE) and ethyl acetate (EtOAc) extracts of Spiranthes sinensis (Pers.) Ames, an edible medicinal plant named "panlongshen" in Chinese that is popularly used in medicinal foods and herbal teas. The structures of the obtained compounds were identified on the basis of extensive NMR spectroscopy and HR-ESI-MS analyses. The cytotoxicities of the phenanthrenes (1-13), the bibenzyl compound (14) , and the flavonoids (15-16 and 20-22) toward SGC-7901, HepG2, and B16-F10 cell lines were examined in vitro. Compounds 1 and 7 exhibited moderate cytotoxic activities toward all of the selected cancer cell lines, and their IC50 values ranged from 19.0 ± 7.3 to 30.2 ± 5.6 µM. Spiranthesphenanthrene A (1) exhibited higher cytotoxic activity than the positive control cisplatin toward the B16-F10 cell line (IC50 = 19.0 ± 7.3 µM). A wound healing assay revealed the inhibition of the migration of B16-F10 cancer cells in a time- and dose-dependent pattern by treatment with 2.5, 5, and 10 µM solutions of compound 1 for 24 and 48 h, respectively. Western blots revealed that compound 1 obviously increased the level of the E-cadherin protein (an epithelial marker) and decreased the levels of the vimentin and N-cadherin proteins (mesenchymal markers). Furthermore, the level of the transcription factor Snail was also obviously decreased by compound 1 in a dose-dependent manner. Taken together, compound 1 inhibits the migration of B16-F10 cancer cells, which may be closely related to the inhibition of the epithelial-mesenchymal transition. Compound 1 represents a promising drug candidate for the prevention of tumor metastasis.

Treatment of Neurodegenerative Diseases with Bioactive Components of Tripterygium wilfordii.

Tripterygium wilfordii Hook F. (TWHF), a traditional Chinese medicine, has been widely used to treat autoimmune and inflammatory diseases including rheumatoid arthritis, systemic lupus erythematosus and dermatomyositis in China. Recently, studies have demonstrated that the bioactive components of TWHF have effective therapeutic potential for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. In this paper, we summarize the research progress of triptolide and celastrol (the two major TWHF components) as well as their analogues in the treatment of neurodegenerative diseases. In addition, we review and discuss the molecular mechanisms and structure features of those two bioactive TWHF components, highlighting their therapeutic promise in neurodegenerative diseases.

Anxiolytic effect of a novel 9,10-dihydrophenanthrene, juncuenin H, is associated with metabolic changes in cortical serotonin/dopamine levels in mice.

Two novel phenanthrenoids, juncuenin H (1) and dijuncuenin B (2), together with eight known phenanthrenoids, effusol (3), dehydroeffusol (4), juncusol (5), dehydrojuncusol (6), juncuenin B (7), dehydrojuncuenin B (8), juncuenin A (9), and dehydrojuncuenin A (10), were isolated from the underground parts of Juncus setchuenensis. The structures of the compounds were determined by 1D and 2D NMR and mass spectroscopy. The anxiolytic activities of compounds 1, 6, 9, and 10 were evaluated. In order to explore the mechanisms underlying their anxiolytic activities, the levels of serotonin (5-HT), dopamine (DA), and their metabolites in the cerebral cortex and hippocampus of mice treated with compound 1 were determined by quantitative mass spectrometry. The mice treated with compound 1 had significantly lower levels of 5-HT, 3-methoxytyramine (3-MT), 5-hydroxyindole-3-acetic acid (5-HIAA), homovanillic acid (HVA), and 3, 4-dihydroxyphenylacetic acid (DOPAC) in the cerebral cortex than those of the vehicle control-treated mice. The levels of HVA and 5-HIAA in the hippocampus were also significantly lower in the mice treated with compound 1 than in the control group mice. These results suggest that the metabolic changes, reflected in the levels of DA and/or 5-HT, may contribute to the anxiolytic activity of the phenanthrenoids studied herein.

Phenanthrene and dihydrophenanthrene derivatives from Dioscorea communis with anticholinesterase, and antioxidant activities.

Five phenanthrene and two dihydrophenanthrene derivatives were isolated from the diethyl ether extract of fresh rhizomes of Dioscorea communis (L.), among them a phenanthrentriol 1 reported for the first time from Dioscoreaceae family and two dihydrophenanthrene derivatives 6 and 7 reported also for the first time from Dioscorea species. The structures of isolated compounds were elucidated using UV, IR, 1D-, 2D-NMR, and MS techniques. The anticholinesterase activity of extracts and four compounds was evaluated for the first time against acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes using Ellman method. Moreover, the antioxidant activity of extracts and three compounds has been investigated using DPPH radical scavenging, ABTS cation radical decolorization, CUPRAC, reducing power and ß-carotene bleaching assays.