Showing papers by "Wen-Cai Ye published in 2016"
TL;DR: The first triketone-phloroglucinol-monoterpene hybrids, callistrilones A and B, along with a postulated biosynthetic intermediate, were isolated from the leaves of Callistemon rigidus and exhibited moderate antibacterial activity against Gram-positive bacteria including multiresistant strains.
66 citations
TL;DR: Five sesquiterpene-based meroterpenoids with three kinds of new skeletons, isolated from the leaves of Myrtus communis, featured a new carbon skeleton with an unprecedented octahydrospiro[bicyclo[7.0]undecane-2,2'-chromene] tetracyclic ring system.
59 citations
TL;DR: Six unusual matrine-type alkaloid dimers, flavesines A-F (1-6, respectively), together with three proposed biosynthetic intermediates (7-9) were isolated from the roots of Sophora flavescens and represented an unprecedented dimerization pattern constructed by matrine and (-)-cytisine.
Abstract: Six unusual matrine-type alkaloid dimers, flavesines A–F (1–6, respectively), together with three proposed biosynthetic intermediates (7–9) were isolated from the roots of Sophora flavescens. Compounds 1–5 were the first natural matrine-type alkaloid dimers, and compound 6 represented an unprecedented dimerization pattern constructed by matrine and (−)-cytisine. Their structures were elucidated by NMR, MS, single-crystal X-ray diffraction, and a chemical method. The hypothetical biogenetic pathways of 1–6 were also proposed. Compounds 1–9 exhibited inhibitory activities against hepatitis B virus.
58 citations
TL;DR: ADHC-AXpn significantly suppressed the growth of MCF-7 cells, induced mitochondrial apoptosis and cell-cycle arrest, and inhibited Raf/MEK/ERK signaling pathway and Akt phosphorylation.
Abstract: Cycloartane triterpenoids exhibited anticancer effects. This study aims to identify any potential novel anticancer cycloartane triterpenoids from Cimicifuga foetida L. rhizome (Sheng ma) and the mode of actions. Cycloartane triterpenoids were isolated from the C. foetida rhizome by a series of column chromatography and identified by IR, MS and NMR. Their anticancer effects on several human cancer cell lines, MCF-7, HepG2, HepG2/ADM, HeLa, and PC3, and normal human mammary epithelial cells MCF10A were investigated by colony formation and MTT assays. Morphological analysis of apoptosis induction was performed by acridine orange/ethidium bromide dual-staining and Hoechst 33258 nuclear staining. The cell-cycle profile and annexin V staining were evaluated by flow cytometry. Apoptosis were investigated by measuring changes in mitochondrial membrane potential and analyzing expression of cell cycle- and apoptosis-related proteins in MCF-7 cells by Western blotting. A novel cycloartane triterpenoid, 25-O-acetyl-7,8-didehydrocimigenol-3-O-β-d-(2-acetyl)xylopyranoside (ADHC-AXpn), together with the known 7,8-didehydrocimigenol-3-O-β-d-xylopyranoside (DHC-Xpn) were isolated. MCF-7 growth was significantly inhibited by ADHC-AXpn in a dose- and time-dependent manner (IC50: 27.81 µM at 48 h; P = 0.004 vs. control at 25 μM for 48 h treatment), and ADHC-AXpn was selectively cytotoxic for cancerous cells (MCF-7, HepG2/ADM, HepG2 and HELA cells) based on its higher IC50 values for normal cells MCF10A (IC50: 78.63 µM at 48 h) than for tumor cells. In MCF-7 cells, ADHC-AXpn induced G2/M cell cycle arrest by mediating cyclin-B1, and CDK1 and its phosphorylation; and induced apoptosis through the mitochondrial-mediated apoptotic pathway, with inhibition of Akt activation. As ADHC-AXpn suppressed phosphorylation of ERK1/2, Raf and Akt proteins in MCF-7 cells, its apoptotic effect might be associated with Raf/MEK/ERK signaling and Akt activation. ADHC-AXpn significantly suppressed the growth of MCF-7 cells, induced mitochondrial apoptosis and cell-cycle arrest, and inhibited Raf/MEK/ERK signaling pathway and Akt phosphorylation.
53 citations
TL;DR: The data suggest that ClC-3 may regulate cell cycle transition between G0/G1 and S phases by up-regulation of the expression of CDK4 and CDK6 through suppression of p21 and p27 expression.
Abstract: It was shown in this study that knockdown of ClC-3 expression by ClC-3 siRNA prevented the activation of hypotonicity-induced chloride currents, and arrested cells at the G0/G1 phase in nasopharyngeal carcinoma CNE-2Z cells. Reconstitution of ClC-3 expression with ClC-3 expression plasmids could rescue the cells from the cell cycle arrest caused by ClC-3 siRNA treatments. Transfection of cells with ClC-3 siRNA decreased the expression of cyclin D1, cyclin dependent kinase 4 and 6, and increased the expression of cyclin dependent kinase inhibitors (CDKIs), p21 and p27. Pretreatments of cells with p21 and p27 siRNAs depleted the inhibitory effects of ClC-3 siRNA on the expression of CDK4 and CDK6, but not on that of cyclin D1, indicating the requirement of p21 and p27 for the inhibitory effects of ClC-3 siRNA on CDK4 and CDK6 expression. ClC-3 siRNA inhibited cells to progress from the G1 phase to the S phase, but pretreatments of cells with p21 and p27 siRNAs abolished the inhibitory effects of ClC-3 siRNA on the cell cycle progress. Our data suggest that ClC-3 may regulate cell cycle transition between G0/G1 and S phases by up-regulation of the expression of CDK4 and CDK6 through suppression of p21 and p27 expression.
36 citations
TL;DR: The isolated compounds were evaluated for their in vitro antiviral activities against respiratory syncytial virus (RSV) and found to have antiviral activity against Eupatorium chinense.
23 citations
TL;DR: B5G9, a piperazidine derivative of 23-hydroxy betulinic acid (23-HBA), showed excellent in vivo anti-HCC effects, with a tumour growth inhibitory rate of greater than 80%, and no significant side effects, and the underlying mechanism was associated with mitochondria-derived ROS overproduction, and mitochondria played essential roles in B5G8-induced cell death.
Abstract: Elevated production of reactive oxygen species (ROS) and an altered redox state have frequently been observed in hepatocellular carcinoma (HCC); therefore, selective killing of HCC cells by chemotherapeutic agents that stimulate ROS generation or impair antioxidant systems may be a feasible approach in HCC chemotherapy. Recently, betulinic acid and its derivatives have attracted attention because they showed anti-cancer effects via a ROS- and mitochondria-related mechanism. However, the source of ROS overproduction and the role of mitochondria were poorly identified, and the weak in vivo antitumour activity of these compounds limits their development as drugs. Cytotoxicity was detected using MTT assays. In vivo anti-HCC effects were assessed using nude mice bearing HepG2 tumour xenografts. Cell cycle analysis, apoptosis rate and mitochondrial membrane potential were measured by flow cytometry. ROS production was detected using a microplate reader or a fluorescence microscope. Changes in gene and protein levels were measured by RT-PCR and western blotting, respectively. Other assays were performed using related detection kits. B5G9, a piperazidine derivative of 23-hydroxy betulinic acid (23-HBA), showed excellent in vivo anti-HCC effects, with a tumour growth inhibitory rate of greater than 80%, and no significant side effects. B5G9 stimulated the production of ROS, which were derived from the mitochondria, but it had no effect on various other antioxidant systems. Moreover, B5G9 induced mitochondrial dysfunction, which was characterized by morphological changes, membrane potential collapse, membrane permeabilization, and decreases in the O2 consumption rate and ATP production. Furthermore, mtDNA-depleted ρ0 HepG2 cells were less sensitive to B5G9 treatment than wt HepG2 cells, indicating the importance of mitochondria in B5G9-induced cell death. We discovered a piperazidine derivative of 23-HBA, B5G9, with excellent anti-HCC effects both in vivo and in vitro and no obvious toxic effects. The underlying mechanism was associated with mitochondria-derived ROS overproduction, and mitochondria played essential roles in B5G9-induced cell death. This study identified a potential agent for anti-HCC therapy and elucidated the mitochondria-related mechanism of BA and its derivatives.
22 citations
TL;DR: First insights into the stereoselective inhibition of NKA by bufadienolides highlight the important role of the hydrophilic moieties at C3 for binding, and may explain why only 3β-hydroxylated bufadiensolides are present as a toxic chemical defence in toad venom.
Abstract: Cardiotonic steroids (CTS) are clinically important drugs for the treatment of heart failure owing to their potent inhibition of cardiac Na+, K+-ATPase (NKA). Bufadienolides constitute one of the two major classes of CTS, but little is known about how they interact with NKA. We report a remarkable stereoselectivity of NKA inhibition by native 3β-hydroxy bufalin over the 3α-isomer, yet replacing the 3β-hydroxy group with larger polar groups in the same configuration enhances inhibitory potency. Binding of the two 13C-labelled glycosyl diastereomers to NKA were studied by solid-state NMR (SSNMR), which revealed interactions of the glucose group of the 3β- derivative with the inhibitory site, but much weaker interactions of the 3α- derivative with the enzyme. Molecular docking simulations suggest that the polar 3β-groups are closer to the hydrophilic amino acid residues in the entrance of the ligand-binding pocket than those with α-configuration. These first insights into the stereoselective inhibition of NKA by bufadienolides highlight the important role of the hydrophilic moieties at C3 for binding, and may explain why only 3β-hydroxylated bufadienolides are present as a toxic chemical defence in toad venom.
22 citations
TL;DR: In this paper, the structures of the new melodinus-type alkaloids, including their absolute configurations, were elucidated on the basis of comprehensive spectroscopic and electronic circular dichroism (ECD) analyses and X-ray diffraction.
Abstract: Nine new melodinus-type alkaloids, melohemsines A-I (1–9), together with eight known ones were isolated from Melodinus hemselyanus. The structures of the new alkaloids, including their absolute configurations, were elucidated on the basis of comprehensive spectroscopic and electronic circular dichroism (ECD) analyses and X-ray diffraction. Compound 1 is the first melodinus-type alkaloid with a 6/6/5/5/6/3 hexacyclic ring skeleton system. Compounds 2–3 are the first natural melodinus-type alkaloids with a reduction in two carbon units at C-20.
20 citations
Journal Article•
TL;DR: It is suggested that Desacetylvinblastine monohydrazide potently inhibits angiogenesis-mediated tumor growth through blockage of the activation of VEGF/VEGFR2 and Gas6/Axl pathways and it might serve as a promising antiangiogenic agent for the cancer therapy.
Abstract: Tumor angiogenic process is regulated by multiple proangiogenic pathways, such as vascular endothelial growth factor receptor 2 (VEGFR2) and Axl receptor tyrosine kinase (Axl). Axl is one of many important factors involved in anti-VEGF resistance. Inhibition of VEGF/VEGFR2 signaling pathway alone fails to block tumor neovascularization. Therefore, discovery of novel agents targeting multiple angiogenesis pathways is in demand. Desacetylvinblastine monohydrazide (DAVLBH), a derivative of vinblastine (VLB), has been reported exhibit an anticancer activity via its cytotoxic effect. However, little attention has been paid to the antiangiogenic properties of DAVLBH. Here, we firstly reported that DAVLBH exerted a more potent antiangiogenic effect than VLB in vitro and in vivo, which was associated with inactivation of VEGF/VEGFR2 and Gas6/Axl signaling pathways. We found that DAVLBH inhibited VEGF- and Gas6-induced HUVECs proliferation, migration, tube formation and vessel sprouts formation in vitro and ex vivo. It significantly inhibited in vivo tumor angiogenesis and tumor growth in HeLa xenografts. It also inhibited Gas6-induced pericytes recruitment to endothelial tubes accompanied with a decrease in expression and activation of Axl. Besides, it could block the compensatory up-regulating expression and activation of Axl in response to bevacizumab treatment in HUVECs. Taken together, our results suggest that DAVLBH potently inhibits angiogenesis-mediated tumor growth through blockage of the activation of VEGF/VEGFR2 and Gas6/Axl pathways and it might serve as a promising antiangiogenic agent for the cancer therapy.
18 citations
TL;DR: Novel natural products with paclitaxel‐likemicrotu‐bule‐stabilizing activity owned their major importance in the clinical treatment of cancer.
Abstract: Four novel taxane derivatives, N-debenzoyl-N-methyl-N-heptanoyl-taxol (1), N-debenzoyl-N-me-thyl-N-octanoyl-taxol (2), N-debenzoyl-N-methyl-N-(4-methylhexanoyl)-taxol (3), and N-debenzoyl-N-methyl-N-[(4Z)-1-oxo-4-tenenoyl]-taxol (4), were isolated from the ethanol extract of the whole plant of Taxus wallichiana.var.mairer. These structures were identified on the basis of extensive spectroscopic analysis, and their antitumor activity was evaluated against MCF-7, A549, and 3-AO cancer cell lines by the MTT method. Compound 3, the most promising one, exhibited encouraging effect with IC50 of 77 nm in MCF-7 cells, which was almost matching that of positive control Taxol. In further mechanism study, the tubulin polymerization assay demonstrated that four compounds caused shifts from the soluble tubulin (depolymerized tubulin) to the particulate tubulin fraction (polymerized) which was similar to Taxol. These results revealed novel natural products with paclitaxel-likemicrotu-bule-stabilizing activity owned their major importance in the clinical treatment of cancer.
TL;DR: Findings collectively identify AO-1 as a beneficial compound to ameliorate the deleterious effects of Aβ on dendrite integrity and cell survival, and may provide new insights on drug discovery of AD.
Abstract: Amyloid-β (Aβ) is one of the major causative agents of Alzheimer's disease (AD), the most common neurodegenerative disorder characterized by progressive cognitive impairment. While effective drugs for AD are currently limited, identifying anti-Aβ compounds from natural products has been shown as a promising strategy which may lead to breakthroughs for new drug candidate discovery. We have previously reported that 7-(4-hydroxyphenyl)-1-phenyl-4E-hepten-3-one (AO-1), a diarylheptanoid extracted from the plant Alpinia officinarum, has strong effects on neuronal differentiation and neurite outgrowth in vitro and in vivo. The present study further uncovers that AO-1 exerts neuroprotective effects against the neurotoxicity caused by Aβ. Under the damage of Aβ oligomers, the major pathological forms of Aβ, dendrites of neurons become atrophic and simplified, but such impairments were substantially alleviated by AO-1 treatment. Moreover, AO-1 reduced apoptotic levels and oxidative stress triggered by Aβ. Further analysis showed that the anti-caspase and dendrite protective effects of AO-1 were dependent on activation of phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathways. These findings collectively identify AO-1 as a beneficial compound to ameliorate the deleterious effects of Aβ on dendrite integrity and cell survival, and may provide new insights on drug discovery of AD.
TL;DR: A series of novel dimeric securinine analogues are identified as potent neurite outgrowth enhancers and may provide insights on drug discovery of neural repair and regeneration.
Abstract: Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine analogues as potent neurite outgrowth enhancers. Compounds 13, 14, 17-19, and 21-23, with different lengths of carbon chain of N,N-dialkyl substituting diacid amide linker between two securinine molecules at C-15 position, exhibited notable positive effects on both neuronal differentiation and neurite extension of neuronal cells. Compound 14, one of the most active compounds, was used as a representative compound for mechanistic studies. Its action on neurite outgrowth was through phosphorylation/activation of multiple signaling molecules including Ca2+/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK) and Akt. These findings collectively identify a new group of beneficial compounds for neuritogenesis, and may provide insights on drug discovery of neural repair and regeneration.
TL;DR: In this article, the discovery of two new norsecurinine-derived alkaloid dimers, norsecurus A and B (1 and 2), was reported.
TL;DR: Results indicated that compound 4 might be valuable to anticancer drug candidates because it could induce G1 phase arrest, upregulate the expression levels of caspases-3, -9, and Bax, and downregulates the expression level of Bcl-2.
TL;DR: The antibacterial activities of compounds (I and II) are evaluated, and (I) is shown to exhibit moderate activity as mentioned in this paper, while (II) exhibits no moderate activity.
Abstract: The antibacterial activities of compounds (I) and (II) are evaluated, and (I) is shown to exhibit moderate activity.
TL;DR: The further mechanistic study showed that these compounds could induce apoptosis and cycle arrest in the G2/M phase in MCF-7 cells and showed strong cytotoxicity with IC50 values less than 0.1 μM.
Abstract: Two new 19-norbufadienolides (1 and 2), one new 14,15-epoxy bufadienolide (3), and eight rare bufadienolide–fatty acid conjugates (4–11), together with four known ones (12–15) were isolated from the eggs of toad Bufo bufo gargarizans. Their chemical structures were elucidated by extensive spectroscopic methods in combination with X-ray diffraction analyses. Furthermore, we tested the inhibitory effect of these compounds against breast cancer cell lines MCF-7 and MDA-MB-231. Most of them showed strong cytotoxicity with IC50 values less than 0.1 μM. The further mechanistic study showed that they could induce apoptosis and cycle arrest in the G2/M phase in MCF-7 cells.
TL;DR: Three new aspidosperma-type alkaloids were isolated from the twigs and leaves of Melodinus suaveolens, and the structures of the new compounds were elucidated by using spectroscopic methods, and circular dichroism experiments.
Abstract: Three new aspidosperma-type alkaloids, 3-oxo-11-hydroxytabersonine (2), 1 1-hydroxytabersonine N-oxide (3) and 11-methoxytabersonine N-oxide (4), along with three known ones were isolated from the twigs and leaves of Melodinus suaveolens. The structures of the new compounds were elucidated by using spectroscopic methods, and circular dichroism experiments. The known compounds were identified by comparing their spectroscopic data with those reported in the literature.
Journal Article•
TL;DR: A new flavonoid, 6??-acetyl-spinosin (12), together with 14 known flavonoids, were isolated from Hovenia acerba and their structures were elucidated by extensive spectroscopic methods.
Abstract: A new flavonoid, 6??-acetyl-spinosin (12), together with 14 known flavonoids, were isolated from Hovenia acerba. Their structures were elucidated by extensive spectroscopic methods. The rotamers of four flavonoid C-glycosides 12–15 was investigated for the first time. All the flavonoids were evaluated for their anti-RSV activity by cytopathic effect (CPE) reduction assay. As a result, five flavonoids, 3, 7, 10, 13, and 14, displayed better antiviral effect against three RSV strains. Plaque reduction assay demonstrated that compound 13 mainly inhibited the intracellular replication of RSV. HPLC analysis indicated that the active compounds 3, 7, and 13 had higher contents in the seeds.
TL;DR: In this paper, the chemical analysis of ASB injection resulted in the isolation of four new related impurities (2, 3, 5, 6), together with two known compounds (1, 4) and two unprecedented photocyclization derivatives of isocopalane diterpene.
Abstract: Andrographolide sodium bisulphite (ASB) injection was widely used in China for the treatment of infectious diseases. The chemical analysis of ASB injection resulted in the isolation of four new related impurities (2, 3, 5, 6), together with two known compounds (1, 4). The structures of the new compounds were elucidated by 1D and 2D NMR, high-resolution mass spectrometry, Mo2(OAc)4-induced circular dichroism and ECD calculation. Among them, 1 and 2 were two unprecedented photocyclization derivatives of isocopalane diterpene. The generation of the primary impurity 1 was proved to be an intramolucular 6-exo carbonyl radical cyclization of ASB through a novel sulfonyl group transfer. This finding furnished a facile photocyclization methodology to afford 1 in good yield with excellent regioselectivity. The possible mechanism for the formation of the related impurities was also discussed.
TL;DR: It is demonstrated that the excitatory effect of CNQX on presynaptic interneurons triggered enhancement of both GABAergic and glycinergic synaptic transmission within the rat hypoglossal nucleus.
TL;DR: This study provides novel insights into arenobufagin-induced HCC cells apoptosis, autophagy and cell cycle arrest, and demonstrates that inhibition of PI3K/Akt/mTOR pathway promotes the development of both autophagic and apoptosis caused by arenobunagin treatment.
Abstract: Backgrounds: Hepatocellular carcinoma (HCC) is a deadly form of cancer without effective chemotherapy so far. Thus, there is an urgent need for novel chemotherapeutic agents for the treatment of HCC. Toad venom is frequently used in the treatment of liver cancer in traditional Chinese medicine. However, the exact component and the precise underlying mechanisms against tumor cells remain unclear. In the present research, we sought to study the antitumor mechanism of arenobufagin, a major active ingredient isolated from toad venom, in HCC cells. Methods and Results: The in vitro and in vivo antitumor activity was measured by colonic formation and HepG2/ADM tumor xenograft, respectively. Arenobufagin-induced HepG2 and HepG2/ADM cell apoptosis was detected by Annexin V-FITC staining and transmission electron microscope. The mitochondrial membrane potential measured by JC-1 staining combined with the changes of expression of Caspase9, Caspase3, PARP, Bax and Bcl-2 in HepG2 and HepG2/ADM cells suggested arenobufagin induced apoptosis via the mitochondrial pathways. Increasing autophagosomes that identified by Cyto-ID® staining and transmission electron microscope were observed in HepG2/ADM cells after arenobufagin treatment. Autophagy-specific inhibitors (e.g. 3-methyladenine, chloroquine and bafilomycin A1), small interfering RNAs target Beclin1 and Atg5 enhance arenobufagin-induced apoptosis, indicated that arenobufagin-mediated autophagy may protects HepG2/ADM cells from undergoing apoptotic cell death. We also demonstrated that inhibition of PI3K/Akt/mTOR pathway promotes the development of both autophagy and apoptosis caused by arenobufagin treatment. In addition, arenobufagin arrested HCC cells in G2 phase was determined by flow cytometry and p-Histone H3 (Ser10) staining. Arenobufagin caused double-strand DNA breaks and triggered the DNA damage response was evaluated by comet assay andγH2AX staining, and these effects were partly via the ATM/ATR-Chk1/Chk2-Cdc25C signaling pathway. We used a synthetic biotinylated arenobufagin-conjugated chemical probe in live cells to show that arenobufagin accumulated mainly in the nucleus. The microscopic thermodynamic parameters measured using isothermal titration calorimetry (ITC) also demonstrated that arenobufagin directly bound to DNA in vitro. The spectral characteristics of DNA (e.g. UV-visible absorption spectrum, circular dichroism spectrum and fluorescence intensity of the ethidium bromide-DNA system) indicated that arenobufagin bound to DNA by intercalation. Molecular modeling suggested arenobufagin intercalated with DNA via hydrogen bonds between arenobufagin and GT base pairs. Conclusion: This study provides novel insights into arenobufagin-induced HCC cells apoptosis, autophagy and cell cycle arrest. It is valuable for the further investigation of the use of arenobufagin in clinical anticancer chemotherapy. Citation Format: Min-Feng Chen, Li-Juan Deng, Wen-Cai Ye, Dong-Mei Zhang. Arenobufagin induces apoptosis, autophagy and cell cycle arrest in hepatocellular carcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1328.
Patent•
04 May 2016
TL;DR: In this article, a 23-hydroxy-betulinic acid fluorescent probe was obtained through connection of a coumarin fluorophore to a 3-hydrox-betulusic acid skeleton.
Abstract: The invention relates to the field of novel 23-hydroxybetulinic acid fluorescent derivative organic synthesis and pharmaceutical chemistry and concretely relates to a 23-hydroxybetulinic acid fluorescent probe obtained through connection of a coumarin fluorophore to a 23-hydroxybetulinic acid skeleton. The invention discloses a use of the 23-hydroxybetulinic acid fluorescent derivative in antineoplastic mechanism research and a potential use of the 23-hydroxybetulinic acid fluorescent derivative in cancer treatment and especially relates to a use of the 23-hydroxybetulinic acid fluorescent probe in detection of target cell localization and uptake under action of 23-hydroxybetulinic acid.