Cassaine diterpenoid dimers isolated from Erythrophleum succirubrum with TRAIL-resistance overcoming activity

Activity-guided fractionation of Erythrophleum succirubrum for TRAIL resistance-overcoming activity led to the isolation of four new cassaine diterpenoid dimers, named erythrophlesins A-D (1-4). Their structures were elucidated by spectral data to show that they have an unsymmetrical dimeric structure through an ester bond between two cassaine diterpenoids. These new compounds were revealed to have a significant reversal effect on TRAIL resistance in human gastric adenocarcinoma (AGS) cells.     

Constituents of Pongamia pinnata isolated in a screening for activity to overcome tumor necrosis factor-related apoptosis-inducing ligand-resistance

In a search for natural products with activity to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance, we performed the bioassay-guided fractionation of a semi mangrove, Pongamia pinnata, collected from Bangladesh, and isolated a new compound, (2S)-(2″,3″:7,8)-furanoflavanone (1), along with six known flavonoids (2-7). Two of the compounds significantly overcame TRAIL-resistance in human gastric adenocarcinoma (AGS) cell lines.     

Effects of Curcumin Analogues DMC and EF24 in Combination with the Cytokine TRAIL against Kidney Cancer

The natural compound curcumin has been shown to have therapeutic potential against a wide range of diseases such as cancer. Curcumin reduces cell viability of renal cell carcinoma (RCC) cells when combined with TNF-related apoptosis-inducing ligand (TRAIL), a cytokine that specifically targets cancer cells, by helping overcome TRAIL resistance. However, the therapeutic effects of curcumin are limited by its low bioavailability. Similar compounds to curcumin with higher bioavailability, such as demethoxycurcumin (DMC) and 3,5-bis(2-fluorobenzylidene)-4-piperidone (EF24), can potentially have similar anticancer effects and show a similar synergy with TRAIL, thus reducing RCC viability. This study aims to show the effects of DMC and EF24 in combination with TRAIL at reducing ACHN cell viability and ACHN cell migration. It also shows the changes in death receptor 4 (DR4) expression after treatment with these compounds individually and in combination with TRAIL, which can play a role in their mechanism of action.     

Human hepatocellular carcinoma cells resist to TRAIL-induced apoptosis,and the resistance is abolished by cisplatin

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, selectively induce apoptosis in various transformed cell lines but not in almost-normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2 and 2 decoy receptors, TRAIL-R3 and TRAIL-R4. However, the determining factors of the sensitivity to TRAIL-induced apoptosis are not clearly understood. Herein, we investigated the expression of TRAIL-R, c-FLIP, FADD-like interleukin-1beta-converting enzyme inhibitory protein, and TRAIL-induced apoptosis in human hepatocellular carcinoma (HCC) cell lines. Seven of ten HCC cell lines showed resistance to TRAIL-induced apoptosis and five of seven TRAIL-resistant cell lines became sensitive to TRAIL by co-treatment with cycloheximide. In HCC cell lines, their TRAIL resistance did not correlate with the basal expression level of TRAIL receptors or c-FLIP, however, in human tissues, TRAIL-R1 and TRAIL-R2 expressions were notably decreased compared to normal counterpart. Cisplatin showed synergistic effect on TRAIL-induced apoptosis in most HCC cell lines regardless of their p53 status and TRAIL-R1 was induced by cisplatin treatment in certain cell lines. Inhibition of nuclear factor K B (NF-kappaB) by SN50, a peptide inhibitor of NF-KB activity, had no effect on TRAIL-induced apoptosis in HCC cells. These results suggest that (a) the majority of human HCC cell lines are resistant to TRAIL-induced apoptosis and cycloheximide-sensitive short-lived antiapoptotic molecule(s) is responsible for this resistance, (b) the expression of TRAIL-R1 and TRAIL-R2 is reduced in HCC tissues, and the increased expression of TRAIL-R1 may be a mechanism of cisplatininduced sensitization to TRAIL-induced apoptosis in some HCC cells, and (c) the activation of NF-kappaB may not be involved in the TRAIL resistance of HCC cells     

Boesenberols I–K,new isopimarane diterpenes from Boesenbergia pandurata with TRAIL-resistance overcoming activity

TRAIL is a promising anticancer agent due to its unique ability to kill tumor cells selectively without harming non-malignant cells. However, some cancer cells are reported to be TRAIL-resistant. Searching potent TRAIL agonist to overcome resistance is an important strategy for its successful use as an anticancer agent. As a part of our continuous research on natural inhibitors, activity-guided fractionation of the MeOH extract of Boesenbergia pandurata rhizomes afforded three (1–3) new isopimarane diterpenes, boesenberols I–K, together with two (4–5) known compounds. The structures of these new compounds were elucidated using HRESIMS, IR, 1D and 2D NMR spectroscopy. All compounds showed TRAIL-resistance overcoming activity.     

A novel 18-norclerodane diterpenoid from the roots of Tinospora sagittata var. yunnanensis

A novel 18-nor-clerodane diterpenoid named sagitone (1) was isolated from the 95% ethanol extract of dry roots of Tinospora sagittata var. yunnanensis together with the five known diterpenoids columbin (2), palmatoside C (3), fibleucin (4), tinophylloloside (5) and epitinophylloloside (6). The structure of the new compound 1 was determined based on MS, IR, 1D and 2D NMR spectral data. The compounds 1-6 did not show significant cytotoxic activity against cancer cell lines K562 and HL-60.     

Arteminolides B,C, and D,new inhibitors of farnesyl protein transferase from Artemisia argyi

Arteminolides B-D (2-4), new farnesyl protein transferase inhibitors, were isolated together with a known arteminolide A (1) and new regioisomers (5-7) of the compounds from the aerial parts of Artemisia argyi. Structures of these compounds were elucidated by spectroscopic methods and chemical conversion. Arteminolides inhibited the farnesyl protein transferase with IC(50) values of 0.7-1 microM, while the regioisomers 5-7 were inactive. In addition, it was proved that the exocyclic double bond of sesquiterpene lactone did not affect the inhibitory activity of arteminolide. The effects of compound 2 on H-Ras processing and cellular growth in H-ras-transformed cells were also evaluated.     

Synthesis, biological and computational study of new Schiff base hydrazones bearing 3-(4-pyridine)-5-mercapto-1,2,4-triazole moiety

A series of new Schiff base hydrazones (compounds 1-16) were synthesized by condensation reaction of 4-amino-3-(4-pyridine)-5-mercapto-1,2,4-triazole with various aldehydes and/or dialdehydes. The structure of the prepared compounds was confirmed by means of 1H NMR, 13C NMR, UV-vis, IR and elemental analyses. The all prepared compounds were assayed for antibacterial (Escherichia coli and Staphylococcus aureus) and antifungal (Candida albicans) activities by disc diffusion method. The results indicate that all tested compounds did not show any antibacterial activity against E. coli, as gram negative bacteria, and antifungal activity against C. albicans. But the compounds 2, 3, 4, 6 and 8 containing 4-Cl, 4-Me, 4-MeO, 2,4-di-Cl and 2-OH substituted phenyl moiety, respectively, showed good inhibition against S. aureus as compare to standard drugs. The structure of all biologically active compounds has also been theoretically studied by ab initio Hartree-Fock (HF) methods.     

Phytochemical and biological activity studies of the Bhutanese medicinal plant Corydalis crispa

The chemical constituents and biological activities of Corydalis crispa (Fumariaceae) were investigated for the first time. The phytochemical study resulted in the isolation of nine known isoquinoline alkaloids: protopine (1), 13-oxoprotopine (2), 13-oxocryptopine (3), stylopine (4), coreximine (5), rheagenine (6), ochrobirine (7), sibiricine (8) and bicuculline (9), with complete NMR data for 2 and 3 provided here for the first time. Crude extracts exhibitedsignificant anti-inflammatory (p < 0.01) activity against TNF-alpha production in LPS activated THP-1 cells. The acetylcholinesterase inhibitory activity of compounds 2, 4 and 7 and the antiplasmodial activity of compound 5 against P. falciparum strains TM4/8.2 and K1CB1 (multidrug resistant strain) are reported here for the first time. Stylopine (4) did not show antimalarial activity against the K1CB1 strain in contrast to a previous report. This study generated a scientific basis for the use of this plant in Bhutanese traditional medicine, either individually or in combination with other medicinal ingredients to treat a broad range of disorders. This study also identified compound 5 as potential new antimalarial lead compound.     

Tupisteroide A–C,three new polyhydroxylated steroidal constituents from the roots of Tupistra chinensis

Three new steroidal compounds with polyhydroxy groups, tupisteroide A–C (1–3), were obtained from the roots of Tupistra chinensis, together with one known compound (4) that was isolated from this plant for the first time. The structures of tupisteroide A–C were determined on the basis of one‐ and two‐dimensional NMR spectroscopy, including ¹H–¹H Correlation Spectroscopy, Heteronuclear Multiple Bond Correlation, and Heteronuclear Single Quantum Coherence experiments. The isolated compounds were evaluated for their cytotoxic activities against A549, HepG2, and CaSki cancer cell lines in vitro. Among them, compounds 1, 2, and 4 did not show significant inhibitory activity, but compound 3 showed cytotoxicity against A549 cancer cell lines with IC₅₀ values of 25.0 μM. Copyright © 2012 John Wiley & Sons, Ltd.     

Phenolic constituents of Cassia seeds and antibacterial effect of some naphthalenes and anthraquinones on methicillin-resistant Staphylococcus aureus.

Thirteen phenolic glycosides including six new compounds were isolated from seeds of Cassia tora (Leguminosae). The structures of the new compounds, rubrofusarin triglucoside (7), nor-rubrofusarin gentiobioside (9), demethylflavasperone gentiobioside (10), torachrysone gentiobioside (11), torachrysone tetraglucoside (12) and torachrysone apioglucoside (13), were elucidated on the basis of spectroscopic and chemical evidence. The effects of the phenolic glycosides, their aglycones and several other compounds structurally related to them on Escherichia coli K12, Pseudomonas aeruginosa PAO1 and some strains of Staphylococcus aureus were then examined. Among them, torachrysone (15), toralactone (16), aloe-emodin (18), rhein (19) and emodin (20) showed noticeable antibacterial effects on four strains of methicillin-resistant Staphylococcus aureus with a minimum inhibitory concentration of 2-64 micrograms/ml. On the other hand, the phenolic compounds tested did not show strong antibacterial effects on E. coli and P. aeruginosa.     

Two new asterosaponins from the Far Eastern starfish Lethasterias fusca

Two new asterosaponins, lethasteriosides A (1) and B (2), were isolated along with previously known thornasteroside A (3), anasteroside A (4), and luidiaquinoside (5) from the ethanolic extract of the Far Eastern starfish Lethasterias fusca. The structures of the new compounds were elucidated by extensive NMR and ESIMS techniques, and chemical transformations. Compounds 1 and 3-5 did not show any apparent cytotoxicity against cancer cell lines T-47D, RPMI-7951, and HCT-116, but glycoside 1, at concentration of 20 microM, demonstrated considerable inhibition of the T-47D (97%), RPMI-795I (90%) and HCT-116 (90%) cell colony formations in a soft agar clonogenic assay.     

Water-soluble constituents of the heartwood of Streblus asper

A new lignan, (7'R,8'R)-threo-strebluslignanol-2-O-beta-D-glucopyranoside, along with 8 known compounds (2-9) were isolated from the water-soluble part of the MeOH extract of the heartwood of Streblus asper. Their structures were elucidated through various spectroscopic methods, including 1D NMR (1H NMR, 13C NMR), 2D NMR (HMQC, HMBC, and NOESY), and HRMS. The stereochemistry at the chiral centers was determined using the CD spectrum, as well as analyses of coupling constants and optical rotation data. In the preliminary bioassay, the isolated compounds did not show anti-HBV activities in vitro using the HBV transfected HepG2.2.15 cell line.     

Acylated flavonol glycosides with anti-complement activity from Persicaria lapathifolia.

During a search for biologically active compounds from traditional medicines, a crude extract of Persicaria lapathifolia was found to have anti-complement activity. Bioassay-guided chromatographic separation of the active constituents led to the isolation of a new acylated kaempferol glycoside (1) and three known acylated quercetin glycosides (2-4). The structures of compounds 1-4 were characterized as kaempferol 3-O-beta-D-(6"-p-hydroxybenzoyl)-galactopyranoside, quercetin 3-O-beta-D-(6"-feruloyl)-galactopyranoside, quercetin 3-O-beta-D-(2"-galloyl)-rhamnopyranoside and quercetin 3-O-beta-D-(2"-galloyl)-glucopyranoside, respectively. Compounds 1-4 showed strong anti-complement activity (IC50 values of 4.3, 9.7, 3.9 and 7.6 x 10(-5) M, respectively) on the classical pathway of the complement. On the other hand, six isolated flavonol glycosides (5-10) did not show any activity on this system.     

苯并呋喃／噻吩联二苯类PTP1B抑制剂三维构效关系研究

主要采用比较分子力场分析方法（CoMFA）对苯并呋喃／噻吩联二苯类PTP1B (protein tyrosine phosphatase 1B)抑制剂进行了三维构效关系的研究，考察了 静电场、立体场和氢键场对构效关系的影响，交叉系数q^2的值达到0．58，表明 CoMFA得到的构效关系模型比较理想，同时test set中分子的预测活性也表明，模 型具有较好的预测能力，研究还表明，氢键场的加入不一定有利于模型的改善，通 过对分子场等值面图的分析，可以观察到叠合分子周围立体场和静电场对化合物活 性的影响，为改进原有化合物的结构，提高它们的活性提供了指导，还尝试采用比 较分子相似性指数分析方法（CoMFA）对这一系列化合物作了研究，结果表明虽然 CoMFA中加入了疏水场，但是对于研究的体系，CoMFA的模型质量并没有显著提高。     

[α-(2-氧代烷基)-α-(取代苯胺基)甲基苯基]-β-D-吡喃阿洛糖苷的合成及镇静活性研究

以豆腐果苷为原料, 通过Mannich反应与取代苯胺和脂肪酮共合成了七个豆腐果苷衍生物, 均未见文献报道. 其结构经¹H NMR, IR, MS和HRMS确认, 并进行了药理活性筛选. 结果表明, 部分化合物均具有良好的镇静活性. 其中, 化合物2a (200 mg/kg), 2b (200 or 100 mg/kg)和2e (200 mg/kg)与豆腐果苷相比较, 具有更强的疗效.     

Synthesis and antibacterial activity of Schiff bases of 5-substituted isatins

Based on the existing reports on the bioactive isatin derivatives, a number of Schiff bases were synthesized by reacting 5-substituted isatins with bioactive amines/hydrazides and their structures were confirmed using spectroscopic methods such as NMR, IR and mass spectrometry. Furthermore, Nbenzylation of isatin followed by the Schiff base formation furnished a new series of compounds(11a–13c) which allowed the analysis of the effect of isatin N-substitution on the bioactivity of the resulting compounds. The antibacterial activity of the synthesized derivatives was evaluated using a microtiter plate method on a series of gram positive and gram negative bacterial strains. Compounds 2d, 3b, 5c and 6a were among the most potent derivatives against Pseudomonas aeruginosa(MIC = 6.25 μg/m L).Analysis of the structure–activity relationship showed that the incorporation of(thio)urea-based Schiff bases lead to more potent derivatives with a broader spectrum of antibacterial activity. In addition,highly lipophilic compounds such as 11a–12c did not show any measurable antibacterial activity, which implies that an optimal lipophilicity might be an important requirement for the antibacterial activity of the studied isatins. Finally, the finding that hydantoin derivatives of N-benzylisatins(13a–13c) still exhibit some antibacterial activity prompted us to consider exploring the bioactivity of more diverse derivatives of isatin-aminohydantoin Schiff bases(compounds 1a–1d) in our future studies.     

Two New Pentacyclic Triterpenoids from Centella asiatica

Two new pentacyclic triterpenoids, named centelloside D ( 1 ) and centelloside E ( 9 ), together with the seven known compounds 2 – 8 , were isolated from the whole plants of Centella asiatica. Compound 5 was reported for the first time from this genus. Their structures were elucidated on the basis of chemical and spectral analysis, including 1D ‐ and 2D ‐NMR, and HR‐MS experiments, and by comparison with literature data. Compounds 1 – 4, 6 , and 8 did not show any cytotoxicity against L929 (mouse embryonic fibroblast).     

Monoterpene glucosides from Ziziphora clinopodioides (Labiatae)

Three new monoterpene glucosides, ziziphoroside A (1), B (2), and C (3), together with fifteen known compounds were isolated from the whole herb of Z. clinopodioides. The structures of new compounds were determined primarily from 1D-, 2D-NMR and circular dichroism (CD) spectroscopic analyses. The isolated compounds were evaluated for their inhibitory activity against nitric oxide (NO) production by lipopolysaccharide (LPS) and interferon (IFN)-γ activated macrophages, RAW 264.7. Shizonepetoside A (8) and flavones (11, 12, 13) showed potent inhibitory activity against NO production.