Black ginger extract and its active compound, 5,7-dimethoxyflavone, increase intestinal drug absorption via efflux drug transporter inhibitions.

Black ginger is used as an herbal medicine for self-care and health promotion. Black ginger extract has been shown to alter the function of transporters in several cell types. This study demonstrates the interaction between the extract and 5,7-dimethoxyflavone (DMF) on drug efflux mediated by breast cancer resistance proteins (BCRP) and P-glycoprotein (P-gp) in Caco-2 cells and heterologous cell systems [Madin-Darby canine kidney type II (MDCKII) stably transfected with human BCRP (MDCKII/BCRP) or human P-gp (MDCKII/P-gp)]. The transepithelial flux of 3H-Digoxin and 3H-Estrone sulfate, prototypic substrates of P-gp, and BCRP, respectively, across Caco-2 cell monolayers, MDCKII/BCRP, and MDCKII/P-gp cells were determined. The results demonstrate that black ginger extract (10 µg/ml) significantly increases 3H-Digoxin and 3H-Estrone sulfate transport from the apical to basolateral side while decreasing transport from the basolateral to apical side of Caco-2 cells and MDCKII cell overexpression of BCRP or P-gp. The effect of the extract on 3H-Digoxin and 3H-Estrone sulfate transport was related to a decrease in efflux ratio. Likewise, DMF (5 µM) significantly increased 3H-Digoxin and 3H-Estrone sulfate absorption with a decreased efflux ratio compared to the control. Interestingly, the extract also significantly increased absorption of paclitaxel, an anti-cancer drug, which has poor oral absorption. Taken together, co-administration of drugs as substrates of BCRP and P-gp, with the black ginger extract containing DMF, might alter the pharmacokinetic profiles of the medicine.

Phyllanthus taxodiifolius Beille Disrupted N-cadherin, Vimentin, Paxillin and Actin Stress Fibers in Glioblastoma.

OBJECTIVE: Glioblastoma is the most aggressive and lethal brain tumor in adults with highly invasive properties. In this present study, we explored the effects of Phyllanthus taxodiifolius Beille extract on molecules known to be hallmarks of aggressive glioblastoma including N-cadherin and vimentin, mesenchymal markers, as well as paxillin, a major adaptor protein that regulates the linking of focal adhesions to the actin cytoskeleton. METHODS: P. taxodiifolius were air-dried, powdered and percolated with methanol, filtered, concentrated and lyophilized to yield a crude methanol extract. C6 glioblastoma cell line was used in this study. The expression of N-cadherin and vimentin, as well as the activation of paxillin was determined using Western blot analysis. The effect of the extract on focal adhesions and actin cytoskeleton were investigated using immunofluorescence staining and confocal imaging. RESULTS: In the presence of 40 µg/ml Phyllanthus taxodiifolius Beille extract, the expression of N-cadherin and vimentin were significantly decreased (p<0.001 and p<0.05, respectively). Activation of paxillin was also diminished as indicated by a reduction of phosphorylated-paxillin (p<0.01). Consequently, actin stress fibers in glioblastoma cells were abolished as evidenced by the decrease in focal adhesion (p<0.001) and stress fibers numbers (p<0.001). CONCLUSION: Our study demonstrates for the first time that P. taxodiifolius interferes with multiple key molecules related to pathological hallmarks of glioblastoma. These molecules are involved with cell contacts, focal adhesions, and the formation and stabilization of actin stress fibers, which are required for glioblastoma metastatic behavior. These results provide further evidence supporting the potential of P. taxodiifolius and its bioactive compounds as anti-cancer agents.

Suppression of PI3K/Akt/mTOR pathway in chrysoeriol-induced apoptosis of rat C6 glioma cells.

Chrysoeriol, a dietary methoxyflavonoid which is found in tropical medicinal plants, has been shown to have antioxidant, anti-inflammatory, and antineoplastic properties. The present study aimed to investigate the effects of chrysoeriol and its related mechanisms in rat C6 glioma cells. Cell viability in rat C6 glioma cells were measured by MTT assay. The protein expression levels of cleaved caspase-3, caspase-3, pro-apoptotic (Bax), anti-apoptotic protein (Bcl-2), and Annexin V were detected by Western blot analysis and immunocytochemical staining. Results showed that chrysoeriol significantly decreased cell viability and induced apoptosis in rat C6 glioma cells. Chrysoeriol significantly increased the levels of Bax/Bcl-2 ratio and cleaved caspase-3/caspase-3 ratio. Moreover, treatment with chrysoeriol significantly reduced the phosphorylation of PI3K, Akt, and mTOR expression in ratios. These results suggest that chrysoeriol promote apoptosis in rat C6 glioma cells via suppression of the PI3K/Akt/mTOR signaling pathway, thereby demonstrating the potential antineoplastic effects of chrysoeriol on glioma cells.

Preparation and Characterization of MUC-30-Loaded Polymeric Micelles against MCF-7 Cell Lines Using Molecular Docking Methods and In Vitro Study.

MUC-30 is a hydrophobic compound which is active against the MCF-7 cancer cell line. In this study, MUC-30 was loaded in polymeric micelles to improve the water solubility and release rate. For prolonged MUC-30 release, MUC-30 was encapsulated in polymeric micelles using PEG-b-PLA and PEG-b-PCL as materials. Micelles prepared with 1 : 9 w per w ratios by film hydration achieved the highest entrapment efficiency (EE%). The EE% of MUC-30-loaded PEG-b-PCL micelles was approximately 30% greater than that of PEG-b-PLA micelles, due to the different H-bond formations between MUC-30 and the polymer membrane (PCL, 4; PLA, 3). The cytotoxic activity of MUC-30 against EGFR theoretically presented 399.31 nM (IC50 = 282.26 ng/mL) by molecular docking. In vitro cytotoxic activity of MUC-30 was confirmed by MTT assay. MUC-30 (IC50 = 11 ± 0.39 ng/mL) showed three-fold higher activity over MUC-30-loaded PEG-b-PLA micelles (IC50 = 37 ± 1.18 ng/mL) and two-fold higher over PEG-b-PCL micelles (IC50 = 75 ± 3.97 ng/mL). This was due to the higher release rate of MUC-30 from PEG-b-PLA micelles compared to PEG-b-PCL micelles. Therefore, MUC-30-loaded PEG-b-PLA micelles could be a promising candidate for breast cancer chemotherapy.

Bioactive tetrahydrofuran lignans from roots, stems, leaves and twigs of Anogeissus rivularis.

Four previously undescribed tetrahydrofuran lignans, named anorisols A-D (1-4) and fourteen known compounds (5-18) were isolated from the roots, stems, leaves and twigs of Anogeissus rivularis. The chemical structures were elucidated on the basis of their spectroscopic data and by comparison with the literature data. The absolute configurations of 1-4 were established by comparison of the experimental ECD spectra with the calculated ECD spectra. Some isolated compounds were evaluated for their cytotoxic activity as well as anti-HIV-1 activity employing reverse transcriptase (RT) and syncytium reduction assays using the ΔTat/RevMC99 virus in 1A2 cell line systems. Compound 6 displayed the most potent activity in syncytium inhibition assay with effective concentration at 50% (EC50) value of 13.3 µM (SI >3.0). In the reverse transcriptase assay, compound 1 exhibited moderate activity with IC50 value of 213.9 µM.

High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component Panduratin A as anti-SARS-CoV-2 agents.

Since December 2019, the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused severe pneumonia, a disease named COVID-19, that became pandemic and created an acute threat to public health. The effective therapeutics are in urgent need. Here, we developed a high-content screening for the antiviral candidates using fluorescence-based SARS-CoV-2 nucleoprotein detection in Vero E6 cells coupled with plaque reduction assay. Among 122 Thai natural products, we found that Boesenbergia rotunda extract and its phytochemical compound, panduratin A, exhibited the potent anti-SARS-CoV-2 activity. Treatment with B. rotunda extract and panduratin A after viral infection drastically suppressed SARS-CoV-2 infectivity in Vero E6 cells with IC50 of 3.62 µg/mL (CC50 = 28.06 µg/mL) and 0.81 µΜ (CC50 = 14.71 µM), respectively. Also, the treatment of panduratin A at the pre-entry phase inhibited SARS-CoV-2 infection with IC50 of 5.30 µM (CC50 = 43.47 µM). Our study demonstrated, for the first time, that panduratin A exerts the inhibitory effect against SARS-CoV-2 infection at both pre-entry and post-infection phases. Apart from Vero E6 cells, treatment with this compound was able to suppress viral infectivity in human airway epithelial cells. This result confirmed the potential of panduratin A as the anti-SARS-CoV-2 agent in the major target cells in human. Since B. rotunda is a culinary herb generally grown in China and Southeast Asia, its extract and the purified panduratin A may serve as the promising candidates for therapeutic purposes with economic advantage during COVID-19 situation.

Anti-HIV-1 activities of constituents from the rhizomes of Boesenbergia thorelii.

A new lignan, thoreliin A (1), and a new bisnorlignan, thoreliin B (2), were isolated from a MeOH extract of the rhizomes of Boesenbergia thorelii. In addition, the known bisnorlignans 3 and 4, neolignan 5, phenylpropanoids 6-15, as well as benzenoids 18-21 were also obtained from the same source. The structures were elucidated based on their spectroscopic data. By single crystal X-ray analysis, the relative stereochemistry of 1 was confirmed. All isolated compounds were evaluated for anti-HIV-1 activities. Among them, thoreliin A (1) exhibited anti-HIV-1 activities on both HIV-1 reverse transcriptase (41.43% inhibition at 200 µg/mL) and syncytium reduction assays (EC50 20.6 µM, SI 3.7), while compounds 3-6, 9 and 11-21 showed anti-HIV-1 activity only in the anti-syncytium assay (EC50 6.6-454.1 µM, SI >1.32-7.75).

Phyllanthus taxodiifolius Beille suppresses microtubule dynamics and restricts glioblastoma aggressiveness.

Glioblastoma is the most common and the most malignant form of brain tumor. This devastating tumor results in death within a year after diagnosis. Although the tumor mass can be surgically removed, glioma cells invade other areas in the brain leading to tumor recurrence and poor prognosis. Therefore, new agents that can overcome cancer cell invasion are urgently required. Phyllanthus taxodiifolius Beille (P. taxodiifolius), has been reported to have potent anti-cancer activities. However, its effects on glioblastoma cells and its underlying mechanisms have never been revealed. Here we investigated the effect and underlying mechanisms of P. taxodiifolius extract on aggressive properties of the glioblastoma, including adhesion, migration, and invasion. P. taxodiifolius extract disrupted adhesion, delayed migration and interfered with the invasion of glioblastoma cells. In addition, the extract suppressed microtubule dynamics as shown by live imaging of a microtubule plus tip protein and decreased focal adhesion by decreasing focal adhesion kinase activity. Our study is the first evidence showing that P. taxodiifolius extract suppresses invasive properties of glioblastoma cells by disrupting microtubule structure and interfering with microtubule dynamics, suggesting the possibility to further develop P. taxodiifolius and its bioactive compounds as an anti-cancer drug targeting microtubules in glioblastoma.

Curcuma comosa reduces visceral adipose tissue and improves dyslipidemia in ovariectomized rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma comosa Roxb. (C. comosa) or Wan chak motluk Zingiberaceae family, is widely used in Thai traditional medicine for treatment of gynecological problems as well as relief of postmenopausal symptoms. Since C. comosa contains phytoestrogen and causes lipid lowering effect by an unknown mechanism, we investigated its effect on adiposity and lipid metabolism in estrogen-deprived rats. MATERIALS AND METHODS: Adult female rats were ovariectomized (OVX) and received daily doses of either a phytoestrogen from C. comosa [(3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol; DPHD], C. comosa extract, or estrogen (17ß-estradiol; E2) for 12 weeks. Adipose tissue mass, serum levels of lipids and adipokines were determined. In addition, genes and proteins involved in lipid synthesis and fatty acid oxidation in visceral adipose tissue were analyzed. RESULTS: Ovariectomy for 12 weeks elevated level of serum lipids and increased visceral fat mass and adipocyte size. These alterations were accompanied with the up-regulation of lipogenic mRNA and protein expressions including LXR-α, SREBP1c and their downstream targets. OVX rats showed decrease in proteins involved in fatty acid oxidation including AMPK-α and PPAR-α in adipose tissue, as well as alteration of adipokines; leptin and adiponectin. Treatments with E2, DPHD or C. comosa extract in OVX rats prevented an increase in adiposity, down-regulated lipogenic genes and proteins with marked increases in the protein levels of AMPK-α and PPAR-α. These findings indicated that their lipid lowering effects were mediated via the suppression of lipid synthesis in concert with an increase in fatty acid oxidation. CONCLUSIONS: C. comosa exerts a lipid lowering effect in the estrogen deficient rats through the modulations of lipid synthesis and AMPK-α activity in adipose tissues, supporting the use of this plant for health promotion in the post-menopausal women.

Marcanine G, a new cytotoxic 1-azaanthraquinone from the stem bark of Goniothalamus marcanii Craib.

The ethanolic extract from the stem bark of Goniothalamus marcanii Craib was shown in preliminary brine shrimp lethality data having good cytotoxic activity. Further bioassay guided isolation was done by means of solvent partition, chromatography and precipitation to provide four isolated compounds: a novel compound 1 with the core structure of 1-azaanthraquinone moiety referred as marcanine G; as well as compounds 2-4 with known aristolactam structures namely, piperolactam C, cepharanone B and taliscanine. These compounds were characterised by spectroscopic techniques. The assessment of cytotoxicity was established on an SRB assay using doxorubicin as a positive control. Marcanine G (1) was considered the most active compound indicating the IC50 values of 14.87 and 15.18 µM against human lung cancer cells (A549) and human breast cancer cells (MCF7), respectively. However, 2 showed mild activity with the IC50 values of 83.72 and 82.32 µM against A549 and MCF7 cells, respectively.

Selective Estrogen Receptor Modulator (SERM)-like Activities of Diarylheptanoid, a Phytoestrogen from Curcuma comosa, in Breast Cancer Cells, Pre-osteoblast Cells, and Rat Uterine Tissues.

Diarylheptanoids from Curcuma comosa, of the Zingiberaceae family, exhibit diverse estrogenic activities. In this study we investigated the estrogenic activity of a major hydroxyl diarylheptanoid, 7-(3,4 -dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene (compound 092) isolated from C. comosa. The compound elicited different transcriptional activities of estrogen agonist at low concentrations (0.1-1 µM) and antagonist at high concentrations (10-50 µM) using luciferase reporter gene assay in HEK-293T cells. In human breast cancer (MCF-7) cells, compound 092 showed an anti-estrogenic activity by down-regulating ERα-signaling and suppressing estrogen-responsive genes, whereas it attenuated the uterotrophic effect of estrogen in immature ovariectomized rats. Of note, compound 092 promoted mouse pre-osteoblastic (MC3T3-E1) cell differentiation and the related bone markers, indicating its positive osteogenic effect. Our findings highlight a new, nonsteroidal, estrogen agonist/antagonist of catechol diarylheptanoid from C. comosa, which is scientific evidence supporting its potential as a dietary supplement to prevent bone loss with low risk of breast and uterine cancers in postmenopausal women.

Protective Effects of a Diarylheptanoid from Curcuma comosa Against Hydrogen Peroxide-Induced Astroglial Cell Death.

Oxidative stress is one of the major mechanisms causing neuronal and astroglial cell death in various neurological disorders such as Alzheimer's disease, Parkinson's disease, and brain ischemia. Two diarylheptanoids, (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (ASPP 049) and (3S)-7-(3,4-dihydroxyphenyl)-1-phenyl-(1E)-1-hepten-3-ol (ASPP 092), isolated from Curcuma comosa were investigated for cytoprotective effects on C6 astroglial cells using hydrogen peroxide (H2O2) exposure as a model of oxidative stress. ASPP 092 demonstrated free radical scavenging activity comparable to that of vitamin C, while ASPP 049 showed no antioxidant activity. Treatment with H2O2 at 400 µM for 12 h caused 79 % C6 astroglial cell death which was significantly reduced to 37 % by pretreatment with ASPP 092 (5 µM). In addition, ASPP 092 attenuated the increase in reactive oxygen species production and the decrease in total glutathione level induced by H2O2. The mechanism of ASPP 092 protection against H2O2-induced apoptotic signaling appeared to involve prevention of increase in the level of phosphorylated p53 and the Bax/Bcl-2 ratio as well as cleaved caspase-3. These findings provide new evidence that the diarylheptanoid ASPP 092 from C. comosa possesses antiapoptotic properties and could be further developed as a potential treatment for oxidative stress-related neuronal diseases.

Potential role of N-benzylcinnamide in inducing neuronal differentiation from human amniotic fluid mesenchymal stem cells.

Neurodegenerative disorders are characterized by chronic and progressive loss of neurons in structure and function related to aging, such as Alzheimer's disease, the latter characterized by the degeneration of cholinergic neurons in basal forebrain connected to the cerebral cortex and hippocampus. Amniotic fluid mesenchymal stem cells (AF-MSCs) have been proposed as one of the candidates for stem cell therapy of nervous system disorders. This study demonstrates that incubation of AF-MSCs, obtained from 16 to 20 week pregnant women, with 10ng/ml bone morphogenetic protein (BMP)-9 for 48h in conditioned medium resulted in transdifferentiation to cholinergic neuronal-like cells. This phenomenon could also be obtained with N-benzylcinnamide (PT-3). Pre-treatment for 1h with 10nM PT-3 augmented BMP-9 transdifferentiation effect, elevated ßIII-tubulin cell numbers and fluorescence intensity of immunoreactive ChAT, ameliorated BMP-9-related production of reactive oxygen species and enhanced anti-apoptosis status of the neuronal-like cells. The transdiffirentiation process was accompanied by increased p53 but decreased Notch1 and SIRT1 (p53 deacetylase) levels, and activation of p38, ERK1/2 MAPK, and PI3K/Akt pathways, in concert with inactivation of JNK, all of which were accentuated by PT-3 pre-treatment. These findings suggest that N-benzylcinnamide may provide a useful adjuvant in BMP-9-induced transdifferentiation of AFMSCs into ultimately cholinergic neurons.

Protective effect of diarylheptanoids from Curcuma comosa on primary rat hepatocytes against t-butyl hydroperoxide-induced toxicity.

CONTEXT: Curcuma comosa Roxb. (Zingiberaceae) has traditionally been used as an anti-inflammatory agent in liver, and recent study has shown its hepatoprotective effect against CCl4-induced liver injury in vivo. OBJECTIVE: This study further assesses the protective effect of C. comosa extracts and its isolated compounds against tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity in isolated primary rat hepatocytes. MATERIALS AND METHODS: Isolated primary hepatocytes were pretreated with either ethanol (5-50 µg/ml) or hexane extract (1-50 µg/ml), or two diarylheptanoids (4-35 µM): compound D-91 [1-(4-hydroxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol] and compound D-92 [(3S)-1-(3,4-dihydroxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol], from C. comosa for 2 h prior to exposure to 1.5 mM t-BHP for 15 and 30 min. Their hepatoprotective activities were then determined. RESULTS: t-BHP markedly caused the formation of MDA and ALT leakage from the hepatocytes. Pretreatment with the C. comosa ethanol extract showed greater protective effect than the hexane extract, and the effect was concentration related. Treating the hepatocytes with compound D-92 provided greater protective effect than compound D-91. IC50 values of compounds D-91, D-92, and silymarin for the protection of ALT leakage at 30 min were 32.7 ± 1.1, 9.8 ± 0.7, and 160 ± 8 µM, respectively. Further investigation showed that compound D-92 was more effective in maintaining the intracellular glutathione content in the t-BHP treated group, whereas the reduction in antioxidant enzymes, glutathione peroxidase and glutathione-S-transferase activities, were not improved. DISCUSSION AND CONCLUSION: Results suggest that diarylheptanoids are the active principles that provide protection against t-BHP-induced injury. Their ability to maintain intracellular glutathione content is the main mechanisms underlying the protective action.

Formal synthesis of (+)-3-epi-eupomatilone-6 and the 3,5-bis-epimer.

The formal synthesis of (+)-3-epi-eupomatilone-6 () and the 3,5-bis-epimer () has been accomplished. The key synthetic strategy involved the stereoselective construction of (3R,4S,5R)- and (3R,4S,5S)-trisubstituted γ-butyrolactones and from (2R,3R)-2,3-dimethyl-4-pentenoic acid derivative , which was readily obtained via stereoselective conjugate addition of vinylmagnesium chloride to a chiral α,ß-unsaturated N-acyl oxazolidinone (Evans' auxiliary) followed by α-methylation.

Curcumin I mediates neuroprotective effect through attenuation of quinoprotein formation, p-p38 MAPK expression, and caspase-3 activation in 6-hydroxydopamine treated SH-SY5Y cells.

6-Hydroxydopamine (6-OHDA) selectively enters dopaminergic neurons and undergoes auto-oxidation resulting in the generation of reactive oxygen species and dopamine quinones, subsequently leading to apoptosis. This mechanism mimics the pathogenesis of Parkinson's disease and has been used to induce experimental Parkinsonism in both in vitro and in vivo systems. In this study, we investigated the effects of curcumin I (diferuloylmethane) purified from Curcuma longa on quinoprotein production, phosphorylation of p38 MAPK (p-p38), and caspase-3 activation in 6-OHDA-treated SH-SY5Y dopaminergic cells. Pretreatment of SH-SY5Y with curcumin I at concentrations of 1, 5, 10, and 20 µM, significantly decreased the formation of quinoprotein and reduced the levels of p-p38 and cleaved caspase-3 in a dose-dependent manner. Moreover, the levels of the dopaminergic neuron marker, phospho-tyrosine hydroxylase (p-TH), were also dose-dependently increased upon treatment with curcumin I. Our results clearly demonstrated that curcumin I protects neurons against oxidative damage, as shown by attenuation of p-p38 expression, caspase-3-activation, and toxic quinoprotein formation, together with the restoration of p-TH levels. This study provides evidence for the therapeutic potential of curcumin I in the chemoprevention of oxidative stress-related neurodegeneration.

A new conjugated amide-dimer from the aerial parts of Piper submultinerve.

Bioassay-guided fractionation and purification of the aerial parts of Piper submultinerve led to the isolation of a new conjugated amide-dimer, submultinamide A (1), along with 11 known compounds. The structures were determined on the basis of spectroscopic methods. Among the tested compounds, pellitorine (2), guineensine (4), N-benzylcinnamide (6) and aristolactam BII (8) showed significant activities in the anti-syncytium assay using (ΔTat/Rev)MC99 virus and 1A2 cell line system, whereas 2 was most active (EC50 35.1 µM and selectivity index 4.7). In the HIV-1 reverse transcriptase assay, only 4 was active with IC50 50.8 µM.

Prenylated caged xanthones: chemistry and biology.

CONTEXT: Prenylated caged xanthones are "privileged structure" characterized by the presence of the unusual 4-oxo-tricyclo[4.3.1.0(3,7)]dec-8-en-2-one scaffold. The natural sources of these compounds confines mainly in the Garcinia genus in the family of Guttiferae. Gambogic acid is the most abundant substance and most of the studies have been done on this compound, particularly as a new potential antitumor agent. The history, sources, structural diversity, and biological activities of these compounds are covered. OBJECTIVE: This review is written with the intention to provide additional aspects from what have been published of prenylated caged xanthones, including history, sources, structural diversity, and biological activities. METHODS: This review has been compiled using information from a number of reliable references mainly from major databases including SciFinder, ScienceDirect, and PubMed. RESULTS: More than 120 prenylated caged xanthones have been found in the plant genera Garcinia, Cratoxylum, and Dascymaschalon. These compounds exhibited various potentially useful biological activities such as anticancer, anti-HIV-1, antibacterial, anti-inflammatory, and neurotrophic activities. CONCLUSIONS: Prenylated caged xanthones, both naturally occurring and synthetic analogues, have been identified as promising bioactive compounds, especially for anticancer agents. Gambogic acid has been demonstrated to be a highly valuable lead compound for antitumor chemotherapy. The structure activity relationship (SAR) study of its analogues is still the subject of intensive research. Apoptosis cytotoxic mechanism has been identified as the major pathway. Research on the delineation of the in-depth mechanism of action is still on-going. Analogues of gambogic acid had been identified to be effective against a rare and special form of liver cancer, cholangiocarcinoma for which currently there is no chemotherapeutic treatment available.

DNA topoisomerase IIα inhibitory and anti-HIV-1 flavones from leaves and twigs of Gardenia carinata.

Four new flavones, 5,2'-dihydroxy-7,3',4',5'-tetramethoxyflavone (1), 5,2',5'-trihydroxy-7,3',4'-trimethoxyflavone (2), 5,7,2',5'-tetrahydroxy-6,3',4'-trimethoxyflavone (3) and 5,2',5'-trihydroxy-6,7,3',4'-tetramethoxyflavone (4), along with the known 5,3'-dihydroxy-6,7,4',5'-tetramethoxyflavone (5), 5,7,3',5'-tetrahydroxy-6,4'-dimethoxyflavone (6), syringaldehyde, vanillic acid and scopoletin were isolated from the leaves and twigs of Gardenia carinata (Rubiaceae). Their structures were determined by spectroscopic methods. Flavone 2 exhibited cytotoxic activity against P-388 and MCF-7 cell lines, while 3, 5 and 6 were active only in P-388 cell line. All active compounds were found to inhibit DNA topoisomerase IIα activity, which may be responsible for the observed cytotoxicity. Flavones 1-3, 5 and 6 also exhibited anti-HIV-1 activity in the anti-syncytium assay using (∆Tat/rev)MC99 virus and 1A2 cell line system; 2 was most potent. Only flavones 1 and 6 showed considerably activity against HIV-1 reverse transcriptase.

Cytotoxic alkaloids from stems, leaves and twigs of Dasymaschalon blumei.

Bioassay-guided fractionation of the cytotoxic ethyl acetate extract from the stems of Dasymaschalon blumei (Annonaceae) led to the isolation of four aristololactam alkaloids, including the hitherto unknown 3,5-dihydroxy-2,4-dimethoxyaristolactam (1), as well as the three known compounds, aristolactam BI, goniopedaline, and griffithinam. Additionally, the cytotoxic extract from the combined leaves and twigs of the same plant yielded three known oxoaporphine alkaloids, oxodiscoguattine, dicentrinone, and duguevalline. The structures of aristolactams and oxoaporphine alkaloids were elucidated on the basis of spectroscopic methods. All isolates were evaluated for cytotoxicity against a panel of mammalian cancer cell lines and a noncancerous human embryonic kidney cell Hek 293.