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Monolithic SiC, for the first time, was seamless joined at a low temperature of 1200 °C using electric field-assisted sintering technology. A 300 nm Yb coating on SiC was used as the joining filler to form Yb3Si2C2 via an in-situ reaction with the SiC. A liquid phase was formed by an eutectic reaction between Yb3Si2C2 and SiC. Almost completely seamless joints were formed by the precipitated SiC grains, which were fully consolidated with the SiC matrix with the help of in-situ formed liquid phase, followed by its elimination under the uniaxial pressure. The bending strength of the seamless joint joined at 1500 °C for 15 min was as high as 257.2 ± 31.1 MPa, which was comparable to the strength of the SiC matrix. As a result, the failure occurred in the matrix indicated a sound joint was obtained. The proposed low temperature seamless joining could potentially be used for joining of SiC-based composite.

The objective of this paper was to develop a PLGA carrier Ticagrelor sustained-release microspheres preparation, which was expected to continue to release Ticagrelor for 14 days with a high encapsulation rate. Ticagrelor microspheres were prepared successfully with average diameter of 7.31 µm, drug loading of 12.49 ± 0.32% and EE up to 79.09 ± 1.69%. In the release medium of PH7.4 PBS, the microspheres showed good drug release behavior in vitro. In vivo release results also showed that the sustained-release microspheres could effectively control drug release in vivo and maintain a relatively stable blood drug concentration for about 2 weeks. The results indicate that Ticagrelor sustained-release microspheres can be used for long-term treatment of acute coronary syndrome.

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered DNA repair enzyme that can repair topoisomerase 2-mediated DNA damage, resulting in cancer cell resistance. In this study, two compounds, robustadial A and B, were isolated from a fraction of the ethyl acetate extract of Eucalyptus globulus Labill. fruits based on TDP2 inhibition screening. The biological experiments indicated that robustadial A and B have TDP2 inhibitory activity with EC50 values of 17 and 42 μM, respectively, but no tyrosyl-DNA phosphodiesterase 1 inhibition at 100 μM. Robustadial A showed significant synergistic effects with the anticancer drug etoposide in four human cancer cell lines, non-small cell lung cancer cell line (A549), prostate cancer cell line (DU145), breast cancer cell line (MCF-7), colorectal adenocarcinoma cell line (HCT-116), and chicken lymphoma cell line (DT40), and chicken lymphoma cell line complementation with human TDP2 (DT40 hTDP2) with combination index values ranging from 0.21 to 0.74. This work will facilitate future efforts for the development of robustadial A-based TDP2 selective inhibitors.

The c-myc oncogene is an important regulator for cell growth and differentiation, and its aberrant overexpression is closely related to the occurrence and development of various cancers. Thus, the suppression of c-myc transcription and expression has been investigated for cancer treatment. In this study, various new bisacridine derivatives were synthesized and evaluated for their binding with c-myc promoter G-quadruplex and i-motif. We found that a9 could bind to and stabilize both G-quadruplex and i-motif, resulting in the downregulation of c-myc gene transcription. a9 could inhibit cancer cell proliferation and induce SiHa cell apoptosis and cycle arrest. a9 exhibited tumor growth inhibition activity in a SiHa xenograft tumor model, which might be related to its binding with c-myc promoter G-quadruplex and i-motif. Our results suggested that a9 as a dual G-quadruplex/i-motif binder could be effective in both oncogene replication and transcription and become a promising lead compound for further development with improved potency and selectivity.

ZTW-41, an indolizinoquinoline-5,12-dione derivative, was investigated for antibacterial activity against Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA). In o...

In order to improve the therapeutic effect, prolong the action time and reduce the side effects of the first generation thrombolytic drug urokinase (UK), a novel UK/multi-walled carbon nanotubes (MWCNTs)-chitosan (CS)-arginine-glycine-aspartic acid (Arg-Gly-Asp) (RGD) drug delivery system was synthesized by chemical bonding/non covalent bond modification/ultrasonic dispersion. The results showed that the diameter of the UK/MWCNTs-CS-RGD drug delivery system was about 30–40 nm, there was a layer of UK was attached to the surface of the tube wall, and the distribution was relatively uniform. The average encapsulation efficiency was 83.10%, and the average drug loading was 12.81%. Interestingly, it also had a certain sustained-release effect, and its release law was best fitted by first-order kinetic equation. Moreover, the accelerated and long-term stability test results show that it had good stability. Compared with free UK, UK/MWCNTs-CS-RGD had thrombolytic effect in vitro. In addition, MTT experiment showed that the prepared MWCNTs-CS-RGD nanomaterials had good biocompatibility. A rabbit model of carotid artery thrombosis was used to conduct targeted thrombolysis experiments in vivo. Compared with free UK, UK/MWCNTs-CS-RGD could be enriched in the thrombosis site to achieve thrombus targeting. UK/MWCNTs-CS-RGD drug delivery system was expected to become an effective thrombolytic drug for targeted therapy of thrombosis.

Purpose:Prunella vulgaris (PV), a traditional Chinese medicine, has been used to treat patients with thyroid disease for centuries in China. The purpose of the present study was to investigate its bioactive ingredients and mechanisms against Hashimoto’s thyroiditis (HT) using network pharmacology and molecular docking technology to provide some basis for experimental research.Methods: Ingredients of the PV formula were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Additionally, HT-related genes were retrieved from the UniProt and GeneCards databases. Cytoscape constructed networks for visualization. A protein–protein interaction (PPI) network analysis was constructed, and a PPI network was built using the Search Tool for the Retrieval of Interacting Genes (STRING) database. These key targets of PV were enriched and analyzed by molecular docking verification, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment.Results: The compound–target network included 11 compounds and 66 target genes. Key targets contained Jun proto-oncogene (JUN), hsp90aa1.1 (AKI), mitogen-activated protein kinase 1 (MAPK1), and tumor protein p53 (TP53). The main pathways included the AGE-RAGE signaling pathway, the TNF signaling pathway, the PI3K–Akt signaling pathway, and the mitogen-activated protein kinase signaling pathway. The molecular docking results revealed that the main compound identified in the Prunella vulgaris was luteolin, followed by kaempferol, which had a strong affinity for HT.Conclusion: Molecular docking studies indicated that luteolin and kaempferol were bioactive compounds of PV and might play an essential role in treating HT by regulating multiple signaling pathways.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a recently discovered enzyme specifically repairing DNA topoisomerase IB-mediated DNA damage, and is a rational anticancer target. Herein, we report the design and synthesis of the first small fluorescent probe 1 as TDP1 substrate. Probe 1 is a specific substrate of TDP1 and shows good spectroscopic properties with more than 140-fold fluorescence enhancement. A novel TDP1 inhibition assay was established using 1 as substrate. The possible cleavage pathway of 1 by TDP1 was also studied.

DNA topoisomerase IB (TOP1) is a validated target for discovery and development of antitumor agents. Four TOP1 poisons are clinically used for tumor treatment now. In spite of their effectiveness in solid tumors, these camptothecin (CPT) poisons suffer from many shortcomings. Therefore, many investigations have focused on the discoveries of non-CPT poisons and catalytic inhibitors. Herein, we systematically study the antitumor activity of CYB-L10, a novel indolizinoquinolinedione TOP1 catalytic inhibitor discovered in our laboratory. The results indicated that CYB-L10 mainly acts on TOP1 in cancer cells and is not a substrate of the P-glycoprotein. In addition, CYB-L10 can induce apoptosis of HCT116 cells, shows high cytotoxicity against 60 human clinical cancer cell lines (NCI60) with the mean-graph midpoint for growth inhibition of all cancer cell lines of 0.050 µM concentration and obvious antitumor efficiency in vivo in the HCT116 xenograft model.

As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links. Inhibiting TDP1 can potentiate the cytotoxicity of TOP1 inhibitors and overcome cancer cell resistance to TOP1 inhibitors. On the basis of our previous study, herein we report the synthesis of benzophenanthridinone derivatives as TOP1 and TDP1 inhibitors. Seven compounds (C2, C4, C5, C7, C8, C12, and C14) showed a robust TOP1 inhibitory activity (+++ or +++ +), and four compounds (A13, C12, C13, and C26) showed a TDP1 inhibition (half-maximal inhibitory concentration values of 15 or 19 μM). We also show that the dual TOP1 and TDP1 inhibitor C12 induces both cellular TOP1cc, TDP1cc formation and DNA damage, resulting in cancer cell apoptosis at a sub-micromolar concentration. In addition, C12 showed an enhanced activity in drug-resistant MCF-7/TDP1 cancer cells and was synergistic with topotecan in both MCF-7 and MCF-7/TDP1 cells.

Based on our previous study on the development of the furoquinolinedione and isoxazoloquinolinedione TDP2 inhibitors, the further structure–activity relationship (SAR) was studied in this work. A series of furoquinolinedione and isoxazoloquinolinedione derivatives were synthesized and tested for enzyme inhibitions. Enzyme-based assays indicated that isoxazoloquinolinedione derivatives selectively showed high TDP2 inhibitory activity at sub-micromolar range, as well as furoquinolinedione derivatives at low micromolar range. The most potent 3-(3,4-dimethoxyphenyl)isoxazolo[4,5-g]quinoline-4,9-dione (70) showed TDP2 inhibitory activity with IC50 of 0.46 ± 0.15 μM. This work will facilitate future efforts for the discovery of isoxazoloquinolinedione TDP2 selective inhibitors.

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor and plays a key role in tumor progression. The C-rich DNA sequence of VEGF promoter can form i-motif structure, which is a potential target for the development of novel anticancer agents. However, there is a limited number of chemotypes as the selective ligands of VEGF promoter i-motif, which leaves much room for development. Herein, we report the discovery of the natural oleanolic acid scaffold as a novel chemotype for the development of selective ligands of VEGF i-motif. A series of oleanolic acid derivatives as VEGF promoter i-motif ligands were synthesized. Subsequent evaluations showed that 3c could selectively bind to and stabilize VEGF promoter i-motif without significant binding to G-quadruplex, duplex DNA, and other oncogene i-motifs. Cell-based assays indicated that 3c could effectively downregulate VEGF gene transcription and expression in MCF-7 cells, inhibit tumor cells proliferation and migration, and induce cancer cells apoptosis. This work provides evidence of VEGF promoter i-motif as an anticancer target and will facilitate future efforts for the discovery of oleanolic acid-based selective ligands of VEGF promoter i-motif.

Spiroconyone A (1), the first rearranged phytosterol featuring an unusual spiro [5,6] ring system, and nine known compounds (2-10) were isolated from the aerial parts of Conyza japonica. The structure of 1 was elucidated through spectroscopic methods, and its absolute configuration was determined by single-crystal X-ray diffraction analysis. Enzyme-based assay revealed that spiroconyone A showed weak TDP1 inhibition and compounds 7 and 10 showed TDP1 inhibition with IC50 values of 36 μM and 16 μM, respectively. MTT assay indicated that 7 and 10 showed a strong synergistic effect with the clinical TOP1 inhibitor topotecan in MCF-7 cells. Compound 5 displayed the most potent cytotoxicity against MCF-7 cells with a GI50 value of 3.3 μM. Furthermore, a hypothetical biosynthetic pathway for 1 was proposed. This work provides valuable information that the secondary metabolites from Conyza japonica could be developed as anticancer agents.

Twelve new polymethylated phloroglucinol meroterpenoids (PPMs), baeckfrutones A–L (1–12), were isolated from the twigs and leaves of Baeckea frutescens. Their structures and absolute configurations were unambiguously established by extensive spectroscopic methods (HRESIMS, NMR, and ECD) and single crystal X-ray diffraction. PPM 1 is a rare PPM comprising enone-type phloroglucinol and α-phellandrene units, whereas 2–4, 6, and 7, are the first hybrids of enone-type phloroglucinol and sabinene moieties with different stereochemistry. (−)-2 and 11 showed remarkable cytotoxicities against DU145 and HCT116 cells with IC50 values of 1.33 and 12.89 μM, respectively. 6, 7, (+)-9, and 10 displayed significant anti-inflammatory activity with inhibitory rates of 74.64, 75.37, 55.13, and 75.01% at the concentration of 50 μM, respectively.

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered enzyme specifically repairing topoisomerase II (TOP2)-mediated DNA damage. It has been shown that inhibition of TDP2 synergize with TOP2 inhibitors. Herein, we report the discovery of the furoquinolinedione chemotype as a suitable skeleton for the development of selective TDP2 inhibitors. Compound 1 was identified as a TDP2 inhibitor as a result of screening our in-house compound library for compounds selective for TDP2 vs. TDP1. Further SAR studies provide several selective TDP2 inhibitors at low-micromolar range. The most potent compound 74 shows inhibitory activity with IC(50) of 1.9 and 2.1 μM against recombinant TDP2 and TDP2 in whole cell extracts (WCE), respectively.

Our previous studies reveal that indolizinoquinolinedione scaffold is a base to develop novel DNA topoisomerase IB (TOP1) catalytic inhibitors. In this work, twenty-three novel indolizinoquinolinedione derivatives were synthesized. TOP1-mediated relaxation, nicking and unwinding assays revealed that three fluorinated derivatives 26, 28 and 29, and one N,N-trans derivative 46 act as TOP1 catalytic inhibitors with higher TOP1 inhibition (++++) than camptothecin (+++) and without TOP1-mediated unwinding effect. MTT assay against five human cancer cell lines indicated that the highest cytotoxicity is 20 for CCRF-CEM cells, 25 for A549 and DU-145 cells, 26 for HCT116 cells, and 33 for Huh7 cells with GI50 values at nanomolar range. The drug-resistant cell assay indicated that compound 26 may mainly act to TOP1 in cells and are less of Pgp substrates. Flow cytometric analysis showed that compounds 26, 28 and 29 can obviously induce apoptosis of HCT116 cells. Moreover, the structure-activity relationship (SAR) of indolizinoquinolinedione derivatives was analyzed.

Eleven new compounds, including six labdane (1-6), three halimane (7-9), and two clerodane (10-11) diterpenoids and 16 known analogues (12-27), were isolated from the leaves of Vitex trifolia. The structures of 1-11 were established by extensive 1D- and 2D-NMR and HRMS spectroscopic data. The absolute configurations of compounds 3, 7, and 10 were assigned using X-ray diffraction. Compounds 1-27 were evaluated for DNA topoisomerases I (Top1) inhibitory activity and cytotoxicity against HCT 116 cells. Compounds 8 and 11 exhibited equipotent Top1 inhibitory activity to the positive control, camptothecin (CPT), at 100μM. Compounds 8, 9, 16, and 27 showed moderate cytotoxicity at low micromolar concentrations.

Callisalignenes G–I (1–3), three new meroterpenoids of β-triketone and monoterpene, along with two known analogues (4 and 5), were isolated from Callistemon salignus. Their structures and absolute configurations were unambiguously established by a combination of NMR and MS analysis and electronic circular dichroism (ECD) evidence. Callisalignenes H (2) and I (3) have a rare sec-butyl moiety at C-7. Meroterpenoids 1–3 exhibited cytotoxicity against HCT116 cells with IC50 values of 8.51 ± 1.8, 9.12 ± 0.3, and 16.33 ± 3.3 μM, respectively. Graphical Abstract Cytotoxic Acylphloroglucinol Derivatives from Callistemon salignus Electronic supplementary material The online version of this article (doi:10.1007/s13659-017-0138-6) contains supplementary material, which is available to authorized users.

Three new acylphloroglucinol derivatives, callisalignones A–C (1–3), six new meroterpenoids, callisalignenes A–F (4–9), along with 18 known analogues (10–27) were isolated from the twigs and leaves of Callistemon salignus. Their structures and absolute configurations were established by comprehensive spectroscopic evidences (NMR, MS, amd electronic circular dichroism calculations). The absolute configurations of callistenones B (13) and H (14) were determined by comparison of their ECD spectra with that of callisalignone B (2). Callisalignones B and C are new adducts of β-triketone and acylphloroglucinol, whereas callisalignenes A–D are new meroterpenoids of acylphloroglucinol and α-phellandrene with different coupling models via hetero-Diels-Alder reaction, respectively. Myrtucommulone D (15) showed significant antibacterial activity against Staphylococcus aureus and three drug resistant S. aureus strains with MIC values of 1.953 and 0.975 μg/mL, respectively. Isomyrtucommulone B (17) displayed remarkable antibacterial activity against Escherichia coli with an MIC value of 0.122 μg/mL. Cytotoxic assay revealed that isomyrtucommulone B (17) was the most active against HCT116 with an IC50 value of 2.09 ± 0.10 μM.

Ten new formyl-phloroglucinol–terpene meroterpenoids, eucalypglobulusals A–J (1–10), and ten known analogues were isolated from Eucalyptus globulus fruits. The structures of 1–10 were determined by spectroscopic analysis, while their absolute configurations were established using calculated and experimental electronic circular dichroism (ECD) spectra. Eucalypglobulusal A was assigned as a new formyl-phloroglucinol–terpene meroterpenoid with a rearranged sesquiterpene skeleton, and an aldol condensation between C-3 and C-5 of the germacrene C moiety was proposed to be a key step in its putative biosynthetic pathway. Eucalypglobulusal F exhibited cytotoxicity against the human acute lymphoblastic cell line (CCRF-CEM) with an IC50 value of 3.3 μM, while eucalypglobulusal A, eucarobustol C, macrocarpal A, macrocarpal B, and macrocarpal D exhibited DNA topoisomerase I (Top1) inhibition. The compounds eucalypglobulusal A and macrocarpal A act as Top1 catalytic inhibitors and delay Top1 poison-mediated DNA doubl...

Lanping basin is a large Pb-Zn-Cu-Ag polymetallic mineral province in SW China, with major deposit types including vein-type Cu deposits, basinal brine-related Pb-Zn deposits (e.g., Liziping, Fulongchang) and minor quartz-vein-type Pb-Zn deposits (e.g., Shangnuluo, Baiji). In this study, we have conducted EPMA and LA-ICP-MS sphalerite trace element analyses, together with gangue carbonate C-O stable isotope analysis and molybdenite Re-Os dating. Using these data, we discuss the mineral assemblage, sphalerite minor/trace element composition, ore-fluid source, and mineralization age of these two types of Pb-Zn deposits. Except sphalerite and galena, major ore minerals from Liziping and Fulongchang are As-rich (e.g., gratonite, jordanite, bournonite, As-rich pyrite), whereas those from Shangnuluo and Baiji are Sb-rich (e.g., boulangerite, jamesonite, stibnite, zinkenite). The trace element compositional characteristics in sphalerite of these deposits (low Mn, Fe, Co, In and Sn, and high Cd) mimic those of medium-low-temperature hydrothermal deposits (MVT and Jinding deposits). For the Liziping zoned sphalerite, the dark-brown zones have relatively high Co, Cu, Ga, As, and Sb; whilst the light-colored zones have relatively high Fe, Mn and Cd. The calculated sphalerite formation temperature based on sphalerite geothermometer – GGIMFis ( Frenzel et al., 2016 ) are basically in agreement with those homogenization temperature of inclusions, indicating that the contents of these elements (Ga, Ge, Fe, Mn and In) in sphalerite are mainly controlled by temperature. Moreover, the estimated sulfur fugacity (log fS2) for Liziping (−14.7) and Fulongchang (−13.6) are distinctly lower than those for Shangnuluo (−7.1) and Baiji (−8.5). Carbonate C–O isotope compositions indicate that the dissolved carbon and oxygen of ore forming-fluids of these Pb-Zn deposits were mainly derived from sedimentary carbonate dissolution. Early-ore-stage molybdenite from Baiji deposit yielded two Re-Os weighted average model ages of 21.4 Ma and 12.93 Ma, and a Re-Os concordia age of 11.88 ± 0.77 Ma was obtained from four younger molybdenite samples. These ages are distinctly younger than those reported mineralization age (ca. 30 Ma) for basinal brine-related Pb-Zn deposits. All these results indicate that there are two different types of Pb-Zn metallogenic events in the northern margin of Lanping Basin.

The Lanping basin is an important Pb-Zn-Cu-Ag polymetallic province in southwestern (SW) China. Mineralization types in the basin include mainly MVT Pb-Zn deposits, vein-type Cu deposits, and minor quartz vein-type Pb-Zn deposits. In this study, we analyzed the total Hg (THg) content and Hg-S isotopic compositions of sulfides from two types of Pb-Zn deposits in the basin, and investigate the Hg isotope fractionation mechanism and its major controlling factors in the Pb-Zn ore-forming process. At the Shangnuluo quartz vein-type Pb-Zn-Sb deposit, sulfides (especially sphalerite) show a wide δ202Hg range (−0.40 to 2.71‰), suggesting that Hg0 evaporation from hydrothermal fluids occurred during the ore formation. Negative THg vs. δ202Hg correlation in the sphalerites suggests a mixing of Hg from the vapor phase (low δ202Hg, high THg) and the residual aqueous phase (high δ202Hg, low THg). The negative ∆199Hg (−0.42 to −0.08‰) suggests that the Hg was sourced from the metamorphic basement, whereas the negative δ34S values (−13.0 to −2.7‰) suggests that the sulfur was mainly sourced from sedimentary sequences, possibly related to the organic matter decomposition and thermochemical sulfate reduction (TSR). For the Liziping and Fulongchang MVT Pb-Zn deposits, sulfides have relatively narrow δ202Hg range (−1.46 to 0.25‰), suggesting limited Hg0 evaporation during the mineralization. Lower δ202Hg values were observed in the early-stage sulfides from these two deposits, probably due to the preferential precipitation of lighter Hg isotopes in these early-stage sulfides. Sulfides from both deposits have negative ∆199Hg values (−0.24 to 0.01‰), suggesting that the Hg was also derived from the metamorphic basement. Sulfide δ34S values from the two deposits are positive, which also suggests that the sulfur was sourced from sedimentary sequences, but mainly related to TSR under relatively low-temperatures. Sulfides from different Pb-Zn deposit types in the Sanjiang Tethyans Metallogenic Belt fall into distinct fields in the δ34S vs. δ202Hg (or ∆199Hg) diagrams, indicating that the integration of S and Hg isotopes is useful to discriminate different types of Pb-Zn deposits.

Based on DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibition of the ethanol extract of the roots of Isodon ternifolius (D. Don) Kudo (Labiatae), its secondary metabolites has been studied. Two new compounds, an ent-abietane diterpenoid isodopene A (1) and a 2,3-seco-triterpene isodopene B (13), along with 25 known compounds were isolated. Their structures were elucidated by spectroscopic analysis and theoretical calculations. The enzyme-based assays indicated that 1 and 13 showed strong (+++) and moderate (++) TOP1 inhibition, respectively. Two chalcone derivatives 11 and 12 were firstly found as dual TDP1 and TOP1 natural inhibitors, and showed synergistic effect with the clinical TOP1 inhibitors topotecan in MCF-7 cells. Compounds 8, 16, and 22 acted as TOP1 catalytic inhibitors with equipotent TOP1 inhibition to camptothecin (++++). Compounds 7 and 8 exhibited significant cytotoxicity against MCF-7, A549, and HCT116 cells with GI50 values in the range of 2.2–4.8 μM. This work would provide valuable information that secondary metabolites from I. ternifolius could be developed as anticancer agents.

Four new sesquiterpenoids, conyterpenols A − D (1–4), along with nineteen known analogues (5–23) were isolated from the aerial parts of Conyza japonica. The structures of 1–4 were determined through spectroscopic analysis, while their absolute configurations were determined by comparison of calculated and experimental electronic circular dichroism (ECD) spectra. Conyterpenol D (4) was a new type of sesquiterpenoid with a seven-membered lactone ring. Compounds 1–23 were evaluated for their inhibitory activity against LPS-induced nitric oxide production in RAW264.7 macrophages and cytotoxicity against human hepatoma cell line (HepG2) and human breast adenocarcinoma cell line (MCF-7). Compounds 3, 4, and 12 displayed moderate inhibition against NO production with IC50 values in the range of 26.4–33.6 μM. And all compounds showed no obvious cytotoxicity against these two cancer cell lines at 100 μM.

Three new spirostanol glycosides, trilliumosides K–M (1–3), one new sesquiterpenoid glycoside, tritschsesuquiside A (4), along with three known analogues (5–7) were obtained from the rhizomes of Trillium tschonoskii. The structures of new glycosides were elucidated by spectroscopic analyses (HRMS and NMR) and chemical methods. Glycosides 5–7 displayed cytotoxicities against five human cancer cell lines with IC50 values ranging from 10.5 ± 1.0 to 1.0 ± 0.2 μM, with 7 being the most cytotoxic compound with IC50 values of 1.0 ± 0.2, 2.2 ± 1.2, and 3.4 ± 0.4 μM against Huh7, CCRF-CEM, and HeLa cell lines, respectively. The flow cytometric results revealed that both 5 and 6 could induce apoptosis of HCT116 and Huh7 cells.

Tyrosyl–DNA phosphodiesterase 1 (TDP1) is a recently discovered enzyme repairing DNA lesions resulting from stalled topoisomerase IB (TOP1)–DNA covalent complex. Inhibiting TDP1 in conjunction with TOP1 inhibitors can boost the action of the latter. Herein, we report the discovery of the natural product oxynitidine scaffold as a novel chemotype for the development of TOP1 and TDP1 inhibitors. Three kinds of analogues, benzophenanthridinone, dihydrobenzophenanthridine, and benzophenanthridine derivatives, were synthesized and evaluated for both TOP1 and TDP1 inhibition and cytotoxicity. Analogue 19a showed high TOP1 inhibition (+++) and induced the formation of cellular TOP1cc and DNA damage, resulting in cancer cells apoptosis at nanomolar concentration range. In vivo studies indicated that 19a exhibits antitumor efficiency in HCT116 xenograft model. 41a exhibited additional TDP1 inhibition with IC(50) value of 7 μM and synergistic effect with camptothecin in MCF-7 cells. This work will facilitate future efforts for the discovery of natural product-based TOP1 and TDP1 inhibitors.

Aberrant overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key feature in oncogenesis and progression of many human cancers. hnRNP K has been found to be a transcriptional activator to up-regulate c-myc gene transcription, a critical proto-oncogene for regulation of cell growth and differentiation. Therefore, down-regulation of c-myc transcription by inhibiting hnRNP K through disrupting its binding to c-myc gene promoter is a potential approach for cancer therapy. In the present study, we synthesized and screened a series of Quinoline derivatives and evaluated their binding affinity for hnRNP K. Among these derivatives, (E)-1-(4-methoxyphenyl)-3-(4-morpholino-6-nitroquinolin-2-yl)prop-2-en-1-one (compound 25) was determined to be the first-reported hnRNP K binding ligand with its KD values of 4.6 and 2.6 μM measured with SPR and MST, respectively. Subsequent evaluation showed that the binding of compound 25 to hnRNP K could disrupt its unfolding of c-myc promoter i-motif, resulting in down-regulation of c-myc transcription. Compound 25 showed a selective anti-proliferative effect on human cancer cell lines with IC50 values ranged from 1.36 to 3.59 μM. Compound 25 exhibited good tumor growth inhibition in a Hela xenograft tumor model, which might be related to its binding with hnRNP K. These findings illustrated that inhibition of DNA-binding protein hnRNP K by compound 25 could be a new and selective strategy of regulating oncogene transcription instead of targeting promoter DNA secondary structures such as G-quadruplexes or i-motifs.

In our previous work, indolizinoquinolinedione derivative 1 was identified as a Top1 catalytic inhibitor. Herein, a series of 6-substituted indolizinoquinolinedione derivatives were synthesized through modification of the parent compound 1. Top1 cleavage and relaxation assays indicate that none of these novel compounds act as classical Top1 poison, and that the compounds with alkylamino terminus at C-6 side chain, including 8, 11-16, 18-21, 25, 26 and 28-30, are the most potent Top1 catalytic inhibitors. Top1-mediated unwinding assay demonstrated that 14, 22 and 26 were Top1 catalytic inhibitors without Top1-mediated unwinding effect. Moreover, MTT results showed that compounds 26, 28-30 exhibit significant cytotoxicity against human leukemia HL-60 cells, and that compound 26 exerts potent cytotoxicity against A549 lung cancer cells at nanomolar range.

Discovery of novel antibacterial agents with new structural scaffolds that combat drug-resistant pathogens is an urgent task. Cajaninstilbene acid, which is isolated from pigeonpea leaves, has shown antibacterial activity. In this study, a series of cajaninstilbene acid derivatives were designed and synthesized. The antibacterial activities of these compounds against gram-negative and gram-positive bacteria, as well as nine strains of methicillin-resistant staphylococcus aureus (MRSA) bacteria are evaluated，and the related structure-activity relationships are discussed. Assays suggest that some of the synthetic cajaninstilbene acid derivatives exhibit potent antibacterial activity against gram-positive bacterial strains and MRSA. Among these compounds, 5b, 5c, 5j and 5k show better antibacterial activity than the positive control compounds. The results of MTT assays illustrate the low cytotoxicity of the active compounds.

G-quadruplexes are four-stranded DNA structures formed from G-rich sequences that are built around tetrads of hydrogen-bonded guanine bases. Accumulating studies have revealed that G-quadruplex structures are formed in vivo and play important roles in biological processes such as DNA replication, transcription, recombination, epigenetic regulation, meiosis, antigenic variation, and maintenance of telomeres stability. Mounting evidence indicates that a variety of proteins are capable of binding selectively and tightly to G-quadruplex and play essential roles in G-quadruplex-mediated regulation processes. Some of these proteins promote the formation or/and stabilization of G-quadruplex, while some other proteins act to unwind G-quadruplex preferentially. From a drug discovery perspective, many of these G-quadruplex binding proteins and/or their complexes with G-quadruplexes are potential drug targets. Here, we present a general summary of reported G-quadruplex binding proteins and their biological functions, with focus on those of medicinal research significance. We elaborated the possibility for some of these G-quadruplex binding proteins and their complexes with G-quadruplexes as potential drug targets.

A phosphorus flame retardant named diphenyl anilinophosphonate (DPAP) was synthesized using diphenyl chlorophosphate and aniline. Its structural features and purity were investigated by mass spectrometry (MS), infrared spectroscopy (IR), nuclear magnetic resonance (NMR) spectroscopy, and high-performance liquid chromatography (HPLC). The thermal properties of DPAP were evaluated using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). A static-analytic method was used to measure the solubilities of DPAP in acetonitrile, methanol, chloroform, ethanol, acetone, toluene, i -propanol, n -propanol, methyl acetate, ethyl acetate, 1,2-dichloroethane, and tetrahydrofuran from 293.15 to 333.15 K. Several thermodynamic models were used to correlate the experimental solubility data, such as the van’t Hoff equation, Buchowski–Ksiazczak ( λh ), Scatchard–Hildebrand, Wilson, nonrandom two-liquid (NRTL), and UNIQUAC. The calculated results showed that these models can reproduce the experimental data well, and that the NRTL equation gives the best correlation. The activity coefficients and solubility parameters of the solute were calculated using the Scatchard–Hildebrand methodology.

Using a static analytical method, the solubilities of phosphonic acid, P,P′-(1,4-piperazinediyl)bis-P,P,P′,P′-tetraphenyl ester (PAPBE), N,N′-[1,3-phenylenebis(methylene)]bis(phosphoramidic acid)P,P,P′,P′-tetraphenyl ester (PNBE), and 4-(hydroxymethyl)-1-oxido-2,6,7-trioxa-1-phosphabicyclo [2.2.2] octane (PEPA) were measured from 293.15 K to 343.15 K in four selected organic solvents. Several thermodynamic models were used to correlate the experimental solubility data, such as Scatchard–Hildebrand, Wilson, nonrandom two-liquid (NRTL), and UNIQUAC. The calculated results showed that all the models reproduced the experimental data very well, and the UNIQUAC equation gives the best correlation. Using the group contribution methods, the solubility parameters of phosphorus flame retardants can be calculated, which were compared with the previous values calculated with the Scatchard–Hildebrand model.

Two novel ruthenium(II) complexes coordinated with 6-chloro-5-hydroxylpyrido[3,2-a]phenazine (CQM), [Ru(L)2(CQM)]ClO4 [L = 1,10-phenanthroline, (1) and 2,2′-bipyridine, (2)], were investigated as potential fluorescent probes to track dynamic changes in the nuclei of living cells. Confocal laser technology was used to observe their co-location inside the cells. The results showed that both complexes were taken up by HepG2 cells, especially 1, which was localized in the cell nuclei, whereas 2 was distributed in the cell nuclei and mitochondria. Further studies by real-time fluorescence observations revealed that 1 rapidly entered the living cells, namely, HepG2, HeLa and MCF-7 cells, imaged the dynamic changes of the nuclei of living tumor cells, and exhibited low toxicity toward cells. The results demonstrated that 1 may be developed into a novel fluorescent probe for living cell nuclei. This study facilitates the development of fluorescent chemosensors with metal complexes.

Psidium guajava L., a species native to South America, has been widely cultivated in the tropical and subtropical areas of China for its popular fruits. The preliminary analysis by liquid chromatography-ultraviolet (LC-UV) indicated the presence of meroterpenoids in the fruits of P. guajava (guava). Subsequent fractionation of the petroleum ether extract resulted in the identification of two new meroterpenoids, psiguajavadials A (1) and B (2), together with 14 previously described meroterpenoids (3–16). Their structures were fully elucidated by comprehensive spectroscopic techniques and theoretical calculations. All of the meroterpenoids showed cytotoxicities against five human cancer cell lines, with guajadial B (12) being the most effective having an IC50 value of 150 nM toward A549 cells. Furthermore, biochemical topoisomerase I (Top1) assay revealed that psiguajavadial A (1), psiguajavadial B (2), guajadial B (12), guajadial C (14), and guajadial F (16) acted as Top1 catalytic inhibitors and delayed T...

A phosphorus-containing flame retardant, bisphenol S-bis (5,5-dimethyl-1,3-dioxaphosphorinanyl-2-oxy phosphate ester) (BSDOPE), was synthesized and characterized by elemental analysis (EA), mass spectra (MS), infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR). The thermal stability of BSDOPE was investigated by thermogravimetric analysis (TGA). The solubilities of flame retardant BSDOPE in selected solvents are measured. Several thermodynamic models, including the ideal, modified Apelblat, Wilson, NRTL, UNIQUAC, the combined Nearly Ideal Binary Solvent (NIBS)/Redlich–Kister, and Scatchard–Hildebrand models, were applied to correlate the experimental solubility data. The results show that the calculated values indicated good agreement with the experimental data.

Using a static analytic method, experimental solubility data were obtained for tetra(5,5-dimethyl-1,3-dioxaphosphorinanyl-2-oxy) neopentane (DOPNP) in acetonitrile, acetone, methanol, ethanol, ethyl acetate, methyl acetate and methylethylketone at temperatures ranging from 293 to 333 K. Several commonly used thermodynamic models, including the ideal, modified Apelblat, Wilson, UNIQUAC and NRTL models, were applied to correlate the experimental solubility data. The binary interaction parameters of the above models were found to have a linear dependency on temperature and the coefficients were regressed. It can be seen that NRTL model is more suitable in describing the solubility data of DOPNP, compared with the other models. By using the van’t Hoff equation, the dissolution enthalpy, dissolution entropy, and Gibbs free energy change of DOPNP are predicted in different pure solvents.

Activity coefficients at infinite dilution for a series of organic solutes in the ionic liquid 1-hexyl-3-methylimidazolium trifluoroacetate ([HMIM][TFA]) have been determined by gas–liquid chromatography at the temperature range from (303.15 to 363.15) K. The contribution of interfacial adsorption to the retention mechanism was estimated by changing the loading of ionic liquid in stationary phase. The partial molar excess enthalpies at infinite dilution and the solubility parameters of ionic liquid were also calculated from the experimental values of activity coefficients at infinite dilution.

Homodimeric proton-translocating pyrophosphatase (H+-PPase; EC 3.6.1.1) maintains the cytoplasmic pH homeostasis of many bacteria and higher plants by coupling pyrophosphate (PPi) hydrolysis and proton translocation. H+-PPase accommodates several essential motifs involved in the catalytic mechanism, including the PPi binding motif and Acidic I and II motifs. In this study, 3 intrinsic tryptophan residues, Trp-75, Trp-365, and Trp-602, in H+-PPase from Clostridium tetani were used as internal probes to monitor the local conformational state of the periplasm domain, transmembrane region, and cytoplasmic domain, respectively. Upon binding of the substrate analog Mg-imidodiphosphate (Mg-IDP), local structural changes prevented the modification of tryptophan residues by N-bromosuccinimide (NBS), especially at Trp-602. Following Mg-Pi binding, Trp-75 and Trp-365, but not Trp-602, were slightly protected from structural modifications by NBS. These results reveal the conformation of H+-PPase is distinct in the presence of different ligands. Moreover, analyses of the Stern-Volmer relationship and steady-state fluorescence anisotropy also indicate that the local structure around Trp-602 is more exposed to solvent and varied under different environments. In addition, Trp-602 was identified to be a crucial residue in the H+-PPase that may potentially be involved in stabilizing the structure of the catalytic region by site-directed mutagenesis analysis.

H⁺-translocating pyrophosphatase (H⁺-PPase, EC 3.6.1.1) plays an important role in acidifying vacuoles by transporting protons across membranes at the expense of pyrophosphate (PP(i)) hydrolysis. Vigna radiata H⁺-PPase (VrH⁺-PPase) contains 16 transmembrane helices (TMs). The hydrophobicity of TM3 is relatively lower than that of most other TMs, and the amino acids in this TM are highly conserved in plants. Furthermore, TM5 and -6, which are the core TMs involving in H⁺-PPase functions, are near TM3. It is thus proposed that TM3 is associated with H⁺-PPase activity. To address this possibility, site-directed mutagenesis was applied in this investigation to determine the role of TM3 in VrH⁺-PPase. Upon alanine/serine substitution, T138 and S142, whose side chains face toward the center TMs, were found to be involved in efficient proton transport. G149/S153 and G160/A164 pairs at the crucial termini of the two GxxxG-like motifs are indispensable in maintaining enzymatic activities and conformational stability. Moreover, stability in the vicinity surrounding G149 is pivotal for efficient expression. S153, M161 and A164 are critical for the K⁺-mediated stimulation of H⁺-PPase. Taken together, our results demonstrate that TM3 plays essential roles in PP(i) hydrolysis, proton transport, expression, and K⁺ stimulation of H⁺-PPase.

A series of pyridophenazine derivatives were synthesized and characterized as DNA intercalating fluorophores. These pyridophenazines showed absorption maxima at ca. 450 nm, and some compounds exhibited strong fluorescence at ca. 530 nm with excellent quantum yields in ethyl acetate solution. DNA binding properties of these pyridophenazines to calf thymus DNA (CT DNA) were studied in phosphate buffered saline at pH 7.4 by means of fluorescence titration. All compounds showed high binding affinity toward CT DNA with binding constant values in the range of 10 6 M −1 , with fluorescence enhancement upon their binding to CT DNA. The fluorescent aminoethylpiperidine substituted pyridophenazine was employed as a sensitive agent for DNA determination with a limit of detection of 65 nM over a linear range of 100–1000 nM. The fluorescence titration and Top1 mediated DNA unwinding assay showed that this derivative exhibited DNA intercalation.

The antibacterial activity of aza-naphthindolizinedione derivatives has been determined. Three compounds, 15, 21 and 40 exhibited strong inhibitory activity against Gram-positive bacterial strains and especially, showed 16 times activity better than vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). Quantitative structure-activity relationship (QSAR) study indicated that the proposed method was a useful computational tool for prediction of antibacterial activity of aza-naphthindolizinedione derivatives. The molecular descriptors contained in the optimized descriptor subsets encoded information about the van der Waals volumes and AlogP of these derivatives and thus implied the relationship between these factors and antibacterial activity. Key words: Aza-naphthindolizinedione derivative, antibacterial agent, methicillin-resistantStaphylococcus aureus, quantitative structure-activity relationship.

To improve the selectivity of indoloquinoline or benzofuroquinoline derivatives, we previously reported several quinazoline derivatives [17]. These compounds could mimic a tetracyclic aromatic system through intramolecular hydrogen bond. Studies showed that these quinazoline derivatives were effective and selective telomeric G-quadruplex ligands. With this encouragement, here we synthesized a series of N-(2-(quinazolin-2-yl)phenyl)benzamide (QPB) compounds as modified quinazoline derivatives. In this modification, a phenyl group was introduced to the aromatic core. The evaluation results showed that part of QPB derivatives had stronger binding ability and better selectivity for telomeric G-quadruplex DNA than LZ-11, the most potential compound of reported quinazoline derivatives. Furthermore, telomerase inhibition of QPB derivatives and their cellular effects were studied.

In our previous research, 9-bromo indolizinoquinoline-5,12-dione 1 has been found to be a good anti-MRSA agent. However, it had very low bioavailability in vivo possibly due to its low solubility in water. In order to obtain the derivatives with higher anti-MRSA activity and good water solubility, twenty eight bromo-substituted indolizinoquinoline-5,12-dione derivatives were synthesized in the present study. The antibacterial activity of the synthesized compounds was evaluated against one gram-negative and some gram-positive bacterial strains including 100 clinical MRSA strains. The UV assays were carried out to determine the solubility of six active compounds 16, 21, 23 and 27–29 . The most potent compound 28 exhibited strong activity against clinical MRSA strains with both MIC 50 and MIC 90 values lower than 7.8 ng/mL. Compound 27 had good water solubility of 1.98 mg/mL and strong activity against clinical MRSA strains with MIC 50 value of 63 ng/mL and MIC 90 value of 125 ng/mL, 16-fold higher than that of Vancomycin.

The surface of polyethylene terephthalate film was modified using RF- Ar/ O2 glow discharge plasma under the condition of Ar and O2 flow amount of 1.9 and 1.2 (L/min) respectively and treatment power of 60 W. The changes of the properties of the film before and after modification were analyzed and characterized with static contact angle measurement, X-ray photoelectron spectroscopy(XPS), atomic force microscopy(AFM), differential scanning calorimetry(DSC). The results showed that the hydrophile of PET film was improved obviously after modification and formed some polar groups such as C-N, N-C=O, C=O, etc. on the film surface; The surface roughness was increased and appeared conical or globular protuberances; the thermal behaviors (mainly crystallinity) were changed after treatment by RF- Ar/O2 plasma.

A series of novel 7-alkoxyl substituted indolizinoquinoline-5,12-dione derivatives were synthesized. The cholinesterase inhibition assays indicated that most synthesized compounds exhibited good activity for acetylcholinesterase (AChE) and high selectivity index of AChE over butyrylcholinesterase (BuChE). Compound 12b exhibited the most potent AChE inhibitory activity with an IC(50) value of 0.068 µM and the highest selectivity index of 144. Kinetic study of AChE indicated that a mixed type of inhibition pattern existed for these indolizinoquinoline-5,12-dione derivatives. Molecular docking study indicated that compound 12b could bind to both the catalytically active site and the peripheral anionic site of AChE.

A series of 9-bromo-substituted indolizinoquinoline-5,12-dione derivatives was synthesized. Antimicrobial activity assessment indicates that compounds 1, 26, 27 and 28 exhibit strong activity against gram-positive bacterial strains, including Beta-hemolytic streptococcus CMCC32210, Staphylococcus aureus ATCC25923, Staphylococcus epidermidis ATCC12228, Enterococcus faecalis ATCC29212 and methicillin-resistant S. aureus ATCC43300 (MRSA). Compound 27 shows the best anti-MRSA activity with an MIC value of 0.031 μg/ml. To assess the mechanism of action, the inhibitory activities of compound 1 against DNA gyrase and DNA topoisomerase IV were also measured. The results indicate that compound 1 has strong inhibitory effects on the Escherichia coli DNA gyrase supercoiling activity and S. aureus Topo IV relaxing activity.

An efficient one-pot synthesis of multi-functionalized chromeno[2,3-c]pyrrol-9(2H)-ones from 1,3-diaryl-1,3-diketones and amino acids is described. The synthesis is based on the 4-(dimethylamino)pyridine-catalyzed Baker–Venkataraman rearrangement and subsequent reactions.