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Articles by Dominique Schols
In JoVE (2)
- Eine kinetische Fluoreszenz basierenden Ca2 + Mobilisierung Assay, G-Protein-gekoppelten Rezeptor-Agonisten und Antagonisten allosterische Modulatoren zu identifizieren
- Ein Flow Cytometry-basierte Assay, Verbindungen zu identifizieren, die Bindung von Eindringmittel beschriftet CXC-Chemokin-Liganden 12 an CXC-Chemokin-Rezeptor 4 stören
Other Publications (44)
- Journal of Virology
- Molecular Pharmacology
- Marine Drugs
- PloS One
- Bioorganic & Medicinal Chemistry
- Transplantation
- European Journal of Medicinal Chemistry
- PLoS Biology
- The Journal of Antimicrobial Chemotherapy
- Carbohydrate Research
- Frontiers in Chemistry
- Bioorganic & Medicinal Chemistry
- Transplant Immunology
- Molecules (Basel, Switzerland)
- Nature Communications
- Archiv Der Pharmazie
- Fertility and Sterility
- Nucleosides, Nucleotides & Nucleic Acids
- European Journal of Medicinal Chemistry
- Bioorganic & Medicinal Chemistry Letters
- Journal of Medicinal Chemistry
- Angewandte Chemie (International Ed. in English)
- PLoS Neglected Tropical Diseases
- Chirality
- MBio
- Molecules (Basel, Switzerland)
- Chemistry (Weinheim an Der Bergstrasse, Germany)
- PloS One
- European Journal of Medicinal Chemistry
- Molecules (Basel, Switzerland)
- Organic & Biomolecular Chemistry
- Scientific Reports
- Scientific Reports
- Monatshefte Fur Chemie
- Antiviral Research
- Medicinal Chemistry (Shariqah (United Arab Emirates))
- PloS One
- Stem Cell Research & Therapy
- Journal of Medicinal Chemistry
- Archiv Der Pharmazie
- PloS One
- European Journal of Medicinal Chemistry
- Molecules (Basel, Switzerland)
- PLoS Pathogens
Articles by Dominique Schols in JoVE
Eine kinetische Fluoreszenz basierenden Ca2 + Mobilisierung Assay, G-Protein-gekoppelten Rezeptor-Agonisten und Antagonisten allosterische Modulatoren zu identifizieren Sandra Claes1, Thomas D'huys1, Anneleen Van Hout1, Dominique Schols1, Tom Van Loy1 1Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven Beschriebenen zelluläre Assay dient zur Identifizierung der CXC-Chemokin-Rezeptor 4 (CXCR4)-interaktiver Agenten, die hemmen oder fördern, kompetitiv oder allosterically, die intrazelluläre Ca2 + Release von CXCR4 Aktivierung initiiert.
Ein Flow Cytometry-basierte Assay, Verbindungen zu identifizieren, die Bindung von Eindringmittel beschriftet CXC-Chemokin-Liganden 12 an CXC-Chemokin-Rezeptor 4 stören Geert Schoofs1, Anneleen Van Hout1, Thomas D'huys1, Dominique Schols1, Tom Van Loy1 1Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven Ein Flow Cytometry-basierten zellulären Bindung Assay beschrieben wird, die in erster Linie als Screening-Instrument verwendet wird, um Verbindungen zu identifizieren, die die Bindung eines Eindringmittel beschrifteten CXC-Chemokin-Liganden 12 (CXCL12) an den CXC-Chemokin-Rezeptor 4 (CXCR4) hemmen.
Other articles by Dominique Schols on PubMed
Mutational Pathways, Resistance Profile, and Side Effects of Cyanovirin Relative to Human Immunodeficiency Virus Type 1 Strains with N-glycan Deletions in Their Gp120 Envelopes Journal of Virology. | Pubmed ID: 16912292 Limited data are available on the genotypic and phenotypic resistance profile of the alpha-(1-2)mannose oligomer-specific prokaryotic lectin cyanovirin (CV-N). Therefore, a more systematic investigation was carried out to obtain a better view of the interaction between CV-N and human immunodeficiency virus type 1 (HIV-1) gp120. When HIV-1-infected CEM cell cultures were exposed to CV-N in a dose-escalating manner, a total of eight different amino acid mutations exclusively located at N-glycosylation sites in the envelope surface gp120 were observed. Six of the eight mutations resulted in the deletion of high-mannose type N-glycans (i.e., at amino acid positions 230, 332, 339, 386, 392, and 448). Two mutations (i.e., at position 136 and 160) deleted a complex type N-glycan in the variable V1/V2 domain of gp120. The level of phenotypic resistance of the mutated virus strains against CV-N generally correlated with the number of glycan deletions in gp120, although deletion of the glycans at N-230, N-392, and N-448 generally afforded a more pronounced CV-N resistance than other N-glycan deletions. However, the extent of the decrease of antiviral activity of CV-N against the mutated virus strains was markedly less pronounced than observed for alpha(1-3)- and alpha(1-6)-mannose-specific plant lectins Hippeastrum hybrid agglutinin (HHA) and Galanthus nivalis agglutinin (GNA), which points to the existence of a higher genetic barrier for CV-N. This is in agreement with a more consistent suppression of a wider variety of HIV-1 clades by CV-N than by HHA and GNA. Whereas the antiviral and in vitro antiproliferative activity of CV-N can be efficiently reversed by mannan, the pronounced mitogenic activity of CV-N on peripheral blood mononuclear cells was unaffected by mannan, indicating that some of the observed side effects of CV-N are unrelated to its carbohydrate specificity/activity.
Carbohydrate-binding Agents Efficiently Prevent Dendritic Cell-specific Intercellular Adhesion Molecule-3-grabbing Nonintegrin (DC-SIGN)-directed HIV-1 Transmission to T Lymphocytes Molecular Pharmacology. | Pubmed ID: 17056872 Exposure of HIV-1 to dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-expressing B-lymphoblast Raji cells (Raji/DC-SIGN) but not to wild-type Raji/0 cells results in the capture of HIV-1 particles to the cells as measured by the quantification of cell-associated p24 antigen. Cocultivation of HIV-1-captured Raji/DC-SIGN cells with uninfected CD4+ T lymphocyte C8166 cells results in abundant formation of syncytia within 36 h after cocultivation. Short preexposure of HIV-1 to carbohydrate-binding agents (CBA) dose dependently prevents the Raji/DC-SIGN cells from efficiently binding the virus particles, and no syncytia formation occurs upon subsequent cocultivation with C8166 cells. Thus, the mannose-specific [i.e., the plant lectins Hippeastrum hybrid agglutinin (HHA), Galanthus nivalis agglutinin (GNA), Narcissus pseudonarcissus agglutinin; and Cymbidium agglutinin (CA); the procaryotic cyanovirin-N (CV-N); and the monoclonal antibody 2G12) and N-acetylglucosamine-specific (i.e., the plant lectin Urtica dioica agglutinin) CBAs efficiently abrogate the DC-SIGN-directed HIV-1 capture and subsequent transmission to T lymphocytes. In this assay, the CD4-down-regulating cyclotriazodisulfonamide derivative, the CXCR4 and CCR5 coreceptor antagonists 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl] - 1,4,8,11 - tetrazacyclotetradecane (AMD3100) and maraviroc, the gp41-binding enfuvirtide, and the polyanionic substances dextran sulfate (M(r) 5000), sulfated polyvinyl alcohol, and the naphthalene sulfonate polymer PRO-2000 were markedly less efficient or even completely ineffective. Similar observations were made in primary monocyte-derived dendritic cell cultures that were infected with HIV-1 particles that had been shortly pre-exposed to the CBAs CV-N, CA, HHA, and GNA and the polyanions DS-5000 and PRO-2000. The potential of CBAs, but not polyanions and other structural/functional classes of entry inhibitors, to impair DC-SIGN-expressing cells in their capacity of transmitting HIV to T lymphocytes might be an important property to be taken into consideration in the eventual choice to move microbicide candidate drugs to the clinical setting.
Algal Lectins As Potential HIV Microbicide Candidates Marine Drugs. | Pubmed ID: 22851920 The development and use of topical microbicides potentially offers an additional strategy to reduce the spread of the Human Immunodeficiency Virus (HIV). Carbohydrate-binding agents (CBAs) that show specificity for high mannose carbohydrates on the surface of the heavily glycosylated envelope of HIV are endowed with potent anti-HIV activity. In fact, a number of algal lectins such as cyanovirin-N, microvirin, microcystis viridis lectin, scytovirin, Oscillatoria agardhii agglutinin and griffithsin are considered as potential microbicide candidates to prevent the sexual transmission of HIV through topical applications. They not only inhibit infection of cells by cell-free virus but they can also efficiently prevent virus transmission from virus-infected cells to uninfected CD4(+) target T-lymphocytes and DC-SIGN-directed capture of HIV-1 and transmission to CD4(+) T lymphocytes. This review focuses on the structural properties and carbohydrate specificity of these algal lectins, their antiviral activity against HIV and several other enveloped viruses, their safety profile and viral resistance patterns.
Sulfated Escherichia Coli K5 Polysaccharide Derivatives Inhibit Dengue Virus Infection of Human Microvascular Endothelial Cells by Interacting with the Viral Envelope Protein E Domain III PloS One. | Pubmed ID: 24015314 Dengue virus (DENV) is an emerging mosquito-borne pathogen that causes cytokine-mediated alterations in the barrier function of the microvascular endothelium, leading to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). We observed that DENV (serotype 2) productively infects primary (HMVEC-d) and immortalized (HMEC-1) human dermal microvascular endothelial cells, despite the absence of well-described DENV receptors, such as dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) or the mannose receptor on the cell surface. However, heparan sulfate proteoglycans (HSPGs) were highly expressed on these cells and pre-treatment of HMEC-1 cells with heparinase II or with glycosaminoglycans reduced DENV infectivity up to 90%, suggesting that DENV uses HSPGs as attachment receptor on microvascular endothelial cells. Sulfated Escherichia coli K5 derivatives, which are structurally similar to heparin/heparan sulfate but lack anticoagulant activity, were able to block DENV infection of HMEC-1 and HMVEC-d cells in the nanomolar range. The highly sulfated K5-OS(H) and K5-N,OS(H) inhibited virus attachment and subsequent entry into microvascular endothelial cells by interacting with the viral envelope (E) protein, as shown by surface plasmon resonance (SPR) analysis using the receptor-binding domain III of the E protein.
Design, Synthesis, Antiviral and Cytostatic Activity of ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates As Acyclic Nucleotide Analogues Bioorganic & Medicinal Chemistry. | Pubmed ID: 24906510 The efficient synthesis of a new series of polyhydroxylated dibenzyl ω-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl ω-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50=20μM-visual CPE score; EC50=18μM-MTS method; MCC >100μM, CC50 >100μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50=9 and 12μM, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50=2.9 and 4μM, respectively) and feline herpes virus in CRFK cells (EC50=4μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC⩾4μM). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC50 in the 4-50μM range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC50 in the 4-7μM range).
Differential Cytokine, Chemokine and Growth Factor Expression in Phenotypes of Chronic Lung Allograft Dysfunction Transplantation. | Pubmed ID: 25050473 Chronic lung allograft dysfunction is a heterogeneous entity limiting long-term survival after lung transplantation. Different clinical phenotypes (bronchiolitis obliterans syndrome [BOS]-neutrophilic BOS-restrictive allograft syndrome [RAS]) have been identified but the mechanisms remain elusive.
2-(4-Chlorobenzyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazoles: Synthesis, Cytotoxic Activity and Mechanism of Action European Journal of Medicinal Chemistry. | Pubmed ID: 25064346 The cytotoxic activity of a new series of 2-(4'-chlorobenzyl)-5,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles against different human and murine cancer cell lines is reported. Among the tested compounds, two derivatives namely 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 4i and 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate 5i emerged as the most potent against all the cell lines. To investigate the mechanism of action, we selected compounds 4i for cell cycle study, analysis of mitochondrial membrane potential and Annexin V-FITC flow cytometric analysis and DNA fragmentation assay. Results showed that 4i induced cytotoxicity by inducing apoptosis without arresting the cell cycle.
Signal Peptide-binding Drug As a Selective Inhibitor of Co-translational Protein Translocation PLoS Biology. | Pubmed ID: 25460167 In eukaryotic cells, surface expression of most type I transmembrane proteins requires translation and simultaneous insertion of the precursor protein into the endoplasmic reticulum (ER) membrane for subsequent routing to the cell surface. This co-translational translocation pathway is initiated when a hydrophobic N-terminal signal peptide (SP) on the nascent protein emerges from the ribosome, binds the cytosolic signal recognition particle (SRP), and targets the ribosome-nascent chain complex to the Sec61 translocon, a universally conserved protein-conducting channel in the ER-membrane. Despite their common function in Sec61 targeting and ER translocation, SPs have diverse but unique primary sequences. Thus, drugs that recognise SPs could be exploited to inhibit translocation of specific proteins into the ER. Here, through flow cytometric analysis the small-molecule macrocycle cyclotriazadisulfonamide (CADA) is identified as a highly selective human CD4 (hCD4) down-modulator. We show that CADA inhibits CD4 biogenesis and that this is due to its ability to inhibit co-translational translocation of CD4 into the lumen of the ER, both in cells as in a cell-free in vitro translation/translocation system. The activity of CADA maps to the cleavable N-terminal SP of hCD4. Moreover, through surface plasmon resonance analysis we were able to show direct binding of CADA to the SP of hCD4 and identify this SP as the target of our drug. Furthermore, CADA locks the SP in the translocon during a post-targeting step, possibly in a folded state, and prevents the translocation of the associated protein into the ER lumen. Instead, the precursor protein is routed to the cytosol for degradation. These findings demonstrate that a synthetic, cell-permeable small-molecule can be developed as a SP-binding drug to selectively inhibit protein translocation and to reversibly regulate the expression of specific target proteins.
Branched-chain Sugar Nucleosides: Stereocontrolled Synthesis and Bioevaluation of Novel 3'-C-trifluoromethyl and 3'-C-methyl Pyranonucleosides Carbohydrate Research. | Pubmed ID: 25812993 A new series of 3'-C-trifluoromethyl- and 3'-C-methyl-β-d-allopyranonucleosides of 5-fluorouracil and their deoxy derivatives has been designed and synthesized. Treatment of ketosugar 1 with trifluoromethyltrimethylsilane under catalytic fluoride activation and methyl magnesium bromide, gave 1,2:5,6-di-O-isopropylidene-3-C-trifluoromethyl (2a) and 3-C-methyl (2b)-α-D-allofuranose, respectively, in a virtually quantitative yield and with complete stereoselectivity. Hydrolysis followed by acetylation led to the 1,2,4,6-tetra-O-acetyl-3-C-trifluoromethyl (3a) and 3-C-methyl (3b)-β-D-allopyranose. Compounds 3a,b were then condensed with silylated 5-fluorouracil and deacetylated to afford the target nucleosides 5a,b. Deoxygenation of the peracylated allopyranoses 3a,b followed by condensation with silylated 5-fluorouracil and subsequent deacetylation yielded the target 3'-deoxy-3'-C-trifluoromethyl and 3'-deoxy-3'-C-methyl-β-d-glucopyranonucleosides 14a,b. The newly synthesized compounds were evaluated for their potential antiviral and cytostatic activities. The 3'-deoxy-3'-C-methyl- ribonucleoside 11b showed significant cytotoxic activity (∼7 μM) almost equally active against a variety of tumor cell lines.
An Easy Microwave-assisted Synthesis of C8-alkynyl Adenine Pyranonucleosides As Novel Cytotoxic Antitumor Agents Frontiers in Chemistry. | Pubmed ID: 25853123 We describe the synthesis of C8-alkynyl adenine pyranonucleosides 4, 5, and 8-phenylethynyl-adenine (II), via Sonogashira cross-coupling reaction under microwave irradiation. Compounds 4e and II were less cytostatic than 5-fluorouracil (almost an order of magnitude) against murine leukemia (L1210) and human cervix carcinoma (HeLa) cells, while the same compounds proved to be more active than 5-fluorouracil against human lymphocyte (CEM) cells.
Design, Antiviral and Cytostatic Properties of Isoxazolidine-containing Amonafide Analogues Bioorganic & Medicinal Chemistry. | Pubmed ID: 26001344 A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesized via cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N-substituted naphthalimide acrylamides and N-allylnaphthalimides. All cis- and trans-isoxazolidine phosphonates obtained herein were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-9d and trans-9f exhibited the highest activity (EC50=8.9μM) toward cytomegalovirus. Compounds cis- and trans-9d as well as cis- and trans-9f were found potent against HSV and Vaccinia viruses (EC50 in the 45-58μM range), whereas isoxazolidines 10a and 10d suppressed replication of Coxsackie B4 and Punta Toro viruses (EC50 in the 45-73μM range). Antiproliferative evaluation of all obtained isoxazolidines revealed the promising activity of cis-9b, cis-9d, trans-9d, cis-9e, trans-9e, cis-9f and trans-9f toward tested cancer cell lines with IC50 in the 1.1-19μM range.
BAL Neutrophilia in Azithromycin-treated Lung Transplant Recipients: Clinical Significance Transplant Immunology. | Pubmed ID: 26168736 Azithromycin decreases airway neutrophilia and can prevent chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx). It also can be used to treat lymphocytic bronchiolitis, as it decreases the submucosal infiltrating IL-17 positive lymphocytes. Some patients, while receiving azithromycin, (re)develop increased airway neutrophilia, which we hypothesize to result in worse outcome and to be regulated by an IL-17-independent mechanism.
Phosphonylated Acyclic Guanosine Analogues with the 1,2,3-Triazole Linker Molecules (Basel, Switzerland). | Pubmed ID: 26501246 A novel series of {4-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates and {4-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates as acyclic analogues of guanosine were synthesized and assessed for antiviral activity against a broad range of DNA and RNA viruses and for their cytostatic activity toward three cancerous cell lines (HeLa, L1210 and CEM). They were devoid of antiviral activity; however, several phosphonates were found slightly cytostatic against HeLa cells at an IC50 in the 80-210 µM range. Compounds (1R,2S)-17k and (1S,2S)-17k showed the highest inhibitory effects (IC50=15-30 µM) against the proliferation of murine leukemia (L1210) and human T-lymphocyte (CEM) cell lines.
Lipophilic Prodrugs of Nucleoside Triphosphates As Biochemical Probes and Potential Antivirals Nature Communications. | Pubmed ID: 26503889 The antiviral activity of nucleoside reverse transcriptase inhibitors is often limited by ineffective phosphorylation. We report on a nucleoside triphosphate (NTP) prodrug approach in which the γ-phosphate of NTPs is bioreversibly modified. A series of TriPPPro-compounds bearing two lipophilic masking units at the γ-phosphate and d4T as a nucleoside analogue are synthesized. Successful delivery of d4TTP is demonstrated in human CD4(+) T-lymphocyte cell extracts by an enzyme-triggered mechanism with high selectivity. In antiviral assays, the compounds are potent inhibitors of HIV-1 and HIV-2 in CD4(+) T-cell (CEM) cultures. Highly lipophilic acyl residues lead to higher membrane permeability that results in intracellular delivery of phosphorylated metabolites in thymidine kinase-deficient CEM/TK(-) cells with higher antiviral activity than the parent nucleoside.
Design, Synthesis, and Antiviral Activity of Novel Ribonucleosides of 1,2,3-Triazolylbenzyl-aminophosphonates Archiv Der Pharmazie. | Pubmed ID: 26575425 A novel series of ribonucleosides of 1,2,3-triazolylbenzyl-aminophosphonates was synthesized through the Kabachnik-Fields reaction using I2 as catalyst followed by copper-catalyzed cycloaddition of the azide-alkyne reaction (CuAAC). All structures of the newly prepared compounds were characterized by (1) H NMR, (13) C NMR, and HRMS spectra. The structures of 2e, 2f, 3d, and 3g were further confirmed by X-ray diffraction analysis. These compounds were tested against various strains of DNA and RNA viruses; compounds 4b and 4c showed a modest inhibitory activity against respiratory syncytial virus (RSV) and compound 4h displayed modest inhibitory activity against Coxsackie virus B4.
Vascular Endothelial Growth Factor Pathway in Endometriosis: Genetic Variants and Plasma Biomarkers Fertility and Sterility. | Pubmed ID: 26773192 To study single nucleotide polymorphisms (SNPs) involved in angiogenesis (VEGF, PLGF, VEGFR1, VEGFR2, HIF-1α) and plasma levels of the corresponding proteins (VEGF, PLGF, sVEGFR1, sVEGFR2) in women with and without endometriosis.
Synthesis and Bioactivity of Novel Trisubstituted Triazole Nucleosides Nucleosides, Nucleotides & Nucleic Acids. | Pubmed ID: 26854981 A series of novel trisubstituted 1,2,3-triazole purine nucleosides were efficiently synthesized via Huisgen 1,3-dipolar cycloaddition in good yields. Bioactivity against cytomegalovirus (CMV) and varicella-zoster virus (VZV) in human embryonic lung cell cultures was evaluated and all compounds show low antiviral activity.
Discovery of Antitumor Anthra[2,3-b]furan-3-carboxamides: Optimization of Synthesis and Evaluation of Antitumor Properties European Journal of Medicinal Chemistry. | Pubmed ID: 26890118 Anthraquinones and their analogues, in particular heteroarene-fused anthracendiones, are prospective scaffolds for new compounds with improved antitumor characteristics. We herein report the use of a 'scaffold hopping' approach for the replacement of the core structure in the previously discovered hit compound naphtho[2,3-f]indole-5,10-dione 2 with an alternative anthra[2,3-b]furan-5,10-dione scaffold. Among 13 newly synthesized derivatives the majority of 4,11-dihydroxy-2-methyl-5,10-dioxoanthra[2,3-b]furan-3-carboxamides demonstrated a high antiproliferative potency against a panel of wild type and drug resistant tumor cell lines, a property superior over the reference drug doxorubicin or lead naphtho[2,3-f]indole-5,10-dione 2. At low micromolar concentrations the selected derivative of (R)-3-aminopyrrolidine 3c and its stereoisomer (S)-3-aminopyrrolidine 3d caused an apoptotic cell death preceded by an arrest in the G2/M phase. Studies of intracellular targets showed that 3c and 3d formed stable intercalative complexes with the duplex DNA as determined by spectral analysis and molecular docking. Both 3c and 3d attenuated topoisomerase 1 and 2 mediated unwinding of the supercoiled DNA via a mechanism different from conventional DNA-enzyme tertiary complex formation. Furthermore, 3d decreased the activity of selected human protein kinases in vitro, indicating multiple targeting by the new chemotype. Finally, 3d demonstrated an antitumor activity in a model of murine intraperitoneally transplanted P388 leukemia, achieving the increase of animal life span up to 262% at tolerable doses. Altogether, the 'scaffold hopping' demonstrated its productivity for obtaining new perspective antitumor drug candidates.
Exploring the Purine Core of 3'-C-ethynyladenosine (EAdo) in Search of Novel Nucleoside Therapeutics Bioorganic & Medicinal Chemistry Letters. | Pubmed ID: 26965865 A series of new nucleoside analogues based on a C-3 branched ethynyl sugar derivative as present in 3'-C-ethynylcytidine (ECyd) and -adenosine (EAdo), combined with modified purine bases was synthetized and evaluated against a broad array of viruses and tumour cell lines. The pronounced cytostatic activity of EAdo was confirmed. EAdo and its 2,6-diaminopurine analogue showed inhibitory activity against vaccinia virus (EC50: 0.31 and 51 μM, respectively). Derivative 10 on the other hand was found active against varicella zoster virus (EC50: 4.68 μM).
Tuning Side Arm Electronics in Unsymmetrical Cyclotriazadisulfonamide (CADA) Endoplasmic Reticulum (ER) Translocation Inhibitors to Improve Their Human Cluster of Differentiation 4 (CD4) Receptor Down-Modulating Potencies Journal of Medicinal Chemistry. | Pubmed ID: 26974263 Cyclotriazadisulfonamide prevents HIV entry into cells by down-modulating surface CD4 receptor expression through binding to the CD4 signal peptide. According to a two-site binding model, 28 new unsymmetrical analogues bearing a benzyl tail group and nine bearing a cyclohexylmethyl tail have been designed and synthesized. The most potent new CD4 down-modulator (40 (CK147); IC50 63 nM) has a 4-dimethylaminobenzenesulfonyl side arm. One of the two side arms was varied with substituents in different positions. This gave a range of CD4 down-modulation potencies that correlated well with anti-HIV-1 activities. The side arms of 21 of the new benzyl-tailed analogues were modeled by means of quantum mechanical calculations. For CADA analogues with arenesulfonamide side arms, the pIC50 values for CD4 down-modulation correlated with the component of the electric dipole moment in the aromatic ring, suggesting that an attractive electronic interaction is a major factor determining the stability of the complex between the molecule and its target.
Membrane-permeable Triphosphate Prodrugs of Nucleoside Analogues Angewandte Chemie (International Ed. in English). | Pubmed ID: 27008042 The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. Rate-limitations can be at the mono-, but also at the di- and triphosphorylation steps. We developed a nucleoside triphosphate (NTP) delivery system (TriPPPro-approach). In this approach, NTPs are masked by two bioreversible units at the γ-phosphate. Using a procedure involving H-phosphonate chemistry, a series of derivatives bearing approved, as well as potentially antivirally active, nucleoside analogues was synthesized. The enzyme-triggered delivery of NTPs was demonstrated by pig liver esterase, in human T-lymphocyte cell extracts and by a polymerase chain reaction using a prodrug of thymidine triphosphate. The TriPPPro-compounds of some HIV-inactive nucleoside analogues showed marked anti-HIV activity. For cellular uptake studies, a fluorescent TriPPPro-compound was prepared that delivered the triphosphorylated metabolite to intact CEM cells.
The Viral Polymerase Inhibitor 7-Deaza-2'-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model PLoS Neglected Tropical Diseases. | Pubmed ID: 27163257 Zika virus (ZIKV) is an emerging flavivirus typically causing a dengue-like febrile illness, but neurological complications, such as microcephaly in newborns, have potentially been linked to this viral infection. We established a panel of in vitro assays to allow the identification of ZIKV inhibitors and demonstrate that the viral polymerase inhibitor 7-deaza-2'-C-methyladenosine (7DMA) efficiently inhibits replication. Infection of AG129 (IFN-α/β and IFN-γ receptor knock-out) mice with ZIKV resulted in acute neutrophilic encephalitis with viral antigens accumulating in neurons of the brain and spinal cord. Additionally, high levels of viral RNA were detected in the spleen, liver and kidney, and levels of IFN-γ and IL-18 were systematically increased in serum of ZIKV-infected mice. Interestingly, the virus was also detected in testicles of infected mice. In line with its in vitro anti-ZIKV activity, 7DMA reduced viremia and delayed virus-induced morbidity and mortality in infected mice, which also validates this small animal model to assess the in vivo efficacy of novel ZIKV inhibitors. Since AG129 mice can generate an antibody response, and have been used in dengue vaccine studies, the model can also be used to assess the efficacy of ZIKV vaccines. .
Synthesis of Novel Chiral Sulfonamide-Bearing 1,2,4-Triazole-3-thione Analogs Derived from D- and L-Phenylalanine Esters As Potential Anti-Influenza Agents Chirality. | Pubmed ID: 27225330 Novel enantiopure 1,2,4-trizole-3-thiones containing a benzensulfonamide moiety were synthesized via multistep reaction sequence starting with D-phenylalanine methyl ester and L-phenylalanine ethyl ester as a source of chirality. The chemical structures of all compounds were characterized by elemental analysis, UV, IR, (1) H NMR, (13) C NMR, 2D NMR (HETCOR), and mass spectral data. All compounds were tested in vitro antiviral activity against a broad variety of DNA and RNA viruses and in vitro cytostatic activity against murine leukemia (L1210), human T-lymphocyte (CEM) and human cervix carcinoma (HeLa) cell lines. Although enantiopure 1,2,4-triazole-3-thione analogs in (R) configuration emerged as promising anti-influenza A H1N1 subtype in Madin Darby canine kidney cell cultures (MDCK), their enantiomers exhibited no activity. Especially compounds , , , , and (EC50 : 6.5, 6.1, 2.4, 1.6, 1.7 μM, respectively) had excellent activity against influenza A H1N1 subtype compared to the reference drug ribavirin (EC50 : 8.0 μM). Several compounds have been found to inhibit proliferation of L1210, CEM and HeLa cell cultures with IC50 in the 12-53 μM range. Compound and in (R) configuration were the most active compounds (IC50 : 12-22 μM for and IC50 : 19-23 μM for ). Chirality 28:495-513, 2016. © 2016 Wiley Periodicals, Inc.
Lectin-Glycan Interaction Network-Based Identification of Host Receptors of Microbial Pathogenic Adhesins MBio. | Pubmed ID: 27406561 The first step in the infection of humans by microbial pathogens is their adherence to host tissue cells, which is frequently based on the binding of carbohydrate-binding proteins (lectin-like adhesins) to human cell receptors that expose glycans. In only a few cases have the human receptors of pathogenic adhesins been described. A novel strategy-based on the construction of a lectin-glycan interaction (LGI) network-to identify the potential human binding receptors for pathogenic adhesins with lectin activity was developed. The new approach is based on linking glycan array screening results of these adhesins to a human glycoprotein database via the construction of an LGI network. This strategy was used to detect human receptors for virulent Escherichia coli (FimH adhesin), and the fungal pathogens Candida albicans (Als1p and Als3p adhesins) and C. glabrata (Epa1, Epa6, and Epa7 adhesins), which cause candidiasis. This LGI network strategy allows the profiling of potential adhesin binding receptors in the host with prioritization, based on experimental binding data, of the most relevant interactions. New potential targets for the selected adhesins were predicted and experimentally confirmed. This methodology was also used to predict lectin interactions with envelope glycoproteins of human-pathogenic viruses. It was shown that this strategy was successful in revealing that the FimH adhesin has anti-HIV activity.
New Isoxazolidine-Conjugates of Quinazolinones-Synthesis, Antiviral and Cytostatic Activity Molecules (Basel, Switzerland). | Pubmed ID: 27455228 A novel series of (3-diethoxyphosphoryl)isoxazolidines substituted at C5 with various quinazolinones have been synthesized by the 1,3-dipolar cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N3-substitued 2-vinyl-3H-quinazolin-4-ones. All isoxazolidines were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-11f/cis-11f (90:10), trans-11h and trans-11i/cis-11i (97:3) showed weak activity (EC50 = 6.84, 15.29 and 9.44 μM) toward VZV (TK⁺ strain) which was only one order of magnitude lower than that of acyclovir used as a reference drug. Phosphonates trans-11b/cis-11b (90:10), trans-11c, trans-11e/cis-11e (90:10) and trans-11g appeared slightly active toward cytomegalovirus (EC50 = 27-45 μM). Compounds containing benzyl substituents at N3 in the quinazolinone skeleton exhibited slight antiproliferative activity towards the tested immortalized cells with IC50 in the 21-102 μM range.
Aspartate-Based CXCR4 Chemokine Receptor Binding of Cross-Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes Chemistry (Weinheim an Der Bergstrasse, Germany). | Pubmed ID: 27458983 The CXCR4 chemokine receptor is implicated in a number of diseases including HIV infection and cancer development and metastasis. Previous studies have demonstrated that configurationally restricted bis-tetraazamacrocyclic metal complexes are high-affinity CXCR4 antagonists. Here, we present the synthesis of Cu(2+) and Zn(2+) acetate complexes of six cross-bridged tetraazamacrocycles to mimic their coordination interaction with the aspartate side chains known to bind them to CXCR4. X-ray crystal structures for three new Cu(2+) acetate complexes and two new Zn(2+) acetate complexes demonstrate metal-ion-dependent differences in the mode of binding the acetate ligand concomitantly with the requisite cis-V-configured cross-bridged tetraazamacrocyle. Concurrent density functional theory molecular modelling studies produced an energetic rationale for the unexpected [Zn(OAc)(H2 O)](+) coordination motif present in all of the Zn(2+) cross-bridged tetraazamacrocycle crystal structures, which differs from the chelating acetate [Zn(OAc)](+) structures of known unbridged and side-bridged tetraazamacrocyclic Zn(2+) -containing CXCR4 antagonists.
Lectin-Like Molecules of Lactobacillus Rhamnosus GG Inhibit Pathogenic Escherichia Coli and Salmonella Biofilm Formation PloS One. | Pubmed ID: 27537843 Increased antibiotic resistance has catalyzed the research on new antibacterial molecules and alternative strategies, such as the application of beneficial bacteria. Since lectin molecules have unique sugar-recognizing capacities, and pathogens are often decorated with sugars that affect their survival and infectivity, we explored whether lectins from the probiotic strain Lactobacillus rhamnosus GG have antipathogenic properties.
Synthesis, Anti-varicella-zoster Virus and Anti-cytomegalovirus Activity of Quinazoline-2,4-diones Containing Isoxazolidine and Phosphonate Substructures European Journal of Medicinal Chemistry. | Pubmed ID: 27750154 Cycloadditions of N-substituted C-(diethoxyphosphoryl)nitrones to N-allylated quinazoline-2,4-diones functionalized at N3 with substituted benzoyl or benzyl groups proceeded with moderate to good diastereoselectivities (d.e. 28-68%). The synthesized isoxazolidine phosphonates were assessed for the antiviral activity against a broad range of DNA and RNA viruses. Compounds trans-13c, cis-13c/trans-13c (86:14), cis-15b/trans-15b (87:13) and trans-15d/cis-15d (95:5) exhibited the highest activity toward both TKand TKVZV strains (mean ECvalues in the range of 3.0-8.7 μM). The EC's for isoxazolidines trans-12a, cis-12a, cis-13a, trans-13d, cis-15a/trans-15a (50:50) ranged between 6.9 and 8.5 μM for VZV TKstrain and between 10.7 and 13.2 μM for VZV TKstrain. The isoxazolidine phosphonates cis-15/trans-15 having benzyl substituents both at N3 of the quinazoline-2,4-dione skeleton and at N2 of the isoxazolidine ring displayed some anti-cytomegalovirus potency but at the same time showed significant cytostatic activity for human embryonic lung fibroblasts (used to carry out the antiviral assays) as well as for other cell lines (i.e. CEM, L1210, HeLa and HMEC-1).
Synthesis and the Biological Activity of Phosphonylated 1,2,3-Triazolenaphthalimide Conjugates Molecules (Basel, Switzerland). | Pubmed ID: 27792200 A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1-benzo[]isoquinolin-2(3)-yl)-methyl]-1-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide was synthesized. All phosphonates were assessed for antiviral activity against a broad range of DNA and RNA viruses and several of them showed potency against varicella-zoster virus (VZV) [EC(50% effective concentration) = 27.6-91.5 μM]. Compoundexhibited the highest activity against a thymidine kinase-deficient (TK) VZV strain (EC= 27.59 μM), whilewas the most potent towards TK⁺ VZV (EC= 29.91 μM). Cytostatic properties of the compounds---were studied on L1210, CEM, HeLa and HMEC-1 cell lines and most of them were slightly cytostatic for HeLa [IC(50% inhibitory concentration) = 29-130 µM] and L1210 cells [IC(50% inhibitory concentration) = 14-142 µM].
Synthesis of Different Types of Alkoxy Fullerene Derivatives from Chlorofullerene CCl Organic & Biomolecular Chemistry. | Pubmed ID: 27830866 We report novel synthetic routes for facile preparation of highly functionalized fullerene derivatives C(OR)X (X = H, Cl, Br), C(OR)O and C(OR)from chlorofullerene CCl. The first water-soluble fullerene compound bearing residues of 3-oxypropanoic acid demonstrated a potent anti-HIV activity.
High Mannose-specific Lectin Msl Mediates Key Interactions of the Vaginal Lactobacillus Plantarum Isolate CMPG5300 Scientific Reports. | Pubmed ID: 27853317 To characterize the interaction potential of the human vaginal isolate Lactobacillus plantarum CMPG5300, its genome was mined for genes encoding lectin-like proteins. cmpg5300.05_29 was identified as the gene encoding a putative mannose-binding lectin. Phenotypic analysis of a gene knock-out mutant of cmpg5300.05_29 showed that expression of this gene is important for auto-aggregation, adhesion to the vaginal epithelial cells, biofilm formation and binding to mannosylated glycans. Purification of the predicted lectin domain of Cmpg5300.05_29 and characterization of its sugar binding capacity confirmed the specificity of the lectin for high- mannose glycans. Therefore, we renamed Cmpg5300.05_29 as a mannose-specific lectin (Msl). The purified lectin domain of Msl could efficiently bind to HIV-1 glycoprotein gp120 and Candida albicans, and showed an inhibitory activity against biofilm formation of uropathogenic Escherichia coli, Staphylococcus aureus and Salmonella Typhimurium. Thus, using a combination of molecular lectin characterization and functional assays, we could show that lectin-sugar interactions play a key role in host and pathogen interactions of a prototype isolate of the vaginal Lactobacillus microbiota.
The Lectin-like Protein 1 in Lactobacillus Rhamnosus GR-1 Mediates Tissue-specific Adherence to Vaginal Epithelium and Inhibits Urogenital Pathogens Scientific Reports. | Pubmed ID: 27869151 The probiotic Lactobacillus rhamnosus GR-1 has been documented to survive implantation onto the vaginal epithelium and interfere with urogenital pathogens. However, the molecular mechanisms involved are largely unknown. Here, we report for the first time the construction of dedicated knock-out mutants in L. rhamnosus GR-1 to enable the study of gene functions. In a search for genes responsible for the adherence capacity of L. rhamnosus GR-1, a genomic region encoding a protein with homology to lectin-like proteins was identified. Phenotypic analyses of the knock-out mutant of L. rhamnosus GR-1 revealed a two-fold decreased adhesion to the vaginal and ectocervical epithelial cell lines compared to wild-type. In contrast, the adhesion to gastro-intestinal epithelial (Caco2) and endocervical cell lines (Hela and End1/E6E7) was not drastically affected by the mutation, suggesting that the LGR-1_Llp1 lectins mediates tissue tropism. The purified LGR-1_Llp1 protein also inhibited biofilm formation and adhesion of uropathogenic Escherichia coli. For the first time, an important role for a novel lectin-like protein in the adhesion capacity and host cell-specific interaction of a vaginal probiotic Lactobacillus strain has been discovered, with an additional role in pathogen inhibition.
Acyclic Nucleoside Phosphonates Containing the Amide Bond Monatshefte Fur Chemie. | Pubmed ID: 27881885 To study the influence of a linker rigidity and donor-acceptor properties, the P-CH-- fragment in acyclic nucleoside phosphonates (e.g., acyclovir, tenofovir) was replaced by the P-CH-- residue. The respective phosphonates were synthesized in good yields by coupling the straight chain of-aminophosphonates and nucleobase-derived acetic acids with EDC. Based on theH andC NMR data, the unrestricted rotation within the methylene and 1,2-ethylidene linkers in phosphonates from seriesandwas confirmed. For phosphonates containing 1,3-propylidene (series) fragments, antiperiplanar disposition of the bulky,-diethylphosphonate and substituted amidomethyl groups was established. The synthesized ANPs P-X-HNC(O)-CHB (X = CH, CHCH, CHCHCH, CHOCHCH) appeared inactive in antiviral assays against a wide variety of DNA and RNA viruses at concentrations up to 100 μM while marginal antiproliferative activity (L1210 cells, IC = 89 ± 16 μM and HeLa cells, IC = 194 ± 19 μM) was noticed for the analog derived from (5-fluorouracyl-1-yl)acetic acid and,-diethyl (2-aminoethoxy)methylphosphonate.
Structure-activity Relationship Studies on a Trp Dendrimer with Dual Activities Against HIV and Enterovirus A71. Modifications on the Amino Acid Antiviral Research. | Pubmed ID: 28017762 We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported.
Synthesis and Ativiral Activity of 5-(Benzylthio)-4-carbamyl-1,2,3-triazoles Against Human Cytomegalovirus (CMV) and Varicella-zoster Virus (VZV) Medicinal Chemistry (Shariqah (United Arab Emirates)). | Pubmed ID: 28290250 All of the clinical drugs for herpesvirus infections exhibit high toxicity and suffer from significant drug-resistantance. There is a great need for the development of new, effective, and safe anti-herpesvirus agents with different mechanisms of action.
Comparison of Cell-based Assays for the Identification and Evaluation of Competitive CXCR4 Inhibitors PloS One. | Pubmed ID: 28410420 The chemokine receptor CXCR4 is activated by its unique chemokine ligand CXCL12 and regulates many physiological and developmental processes such as hematopoietic cell trafficking. CXCR4 is also one of the main co-receptors for human immunodeficiency virus (HIV) entry. Dysfunction of the CXCL12/CXCR4 axis contributes to several human pathologies, including cancer and inflammatory diseases. Consequently, inhibition of CXCR4 activation is recognized as an attractive target for therapeutic intervention. In this regard, numerous agents modifying CXCR4 activity have been evaluated in in vitro experimental studies and pre-clinical models. Here, we evaluated a CXCL12 competition binding assay for its potential as a valuable initial screen for functional and competitive CXCR4 inhibitors. In total, 11 structurally diverse compounds were included in a side-by-side comparison of in vitro CXCR4 cell-based assays, such as CXCL12 competition binding, CXCL12-induced calcium signaling, CXCR4 internalization, CXCL12-guided cell migration and CXCR4-specific HIV-1 replication experiments. Our data indicated that agents that inhibit CXCL12 binding, i.e. the anti-CXCR4 peptide analogs T22, T140 and TC14012 and the small molecule antagonists AMD3100, AMD3465, AMD11070 and IT1t showed inhibitory activity with consistent relative potencies in all further applied CXCR4-related assays. Accordingly, agents exerting no or very weak receptor binding (i.e., CTCE-9908, WZ811, Me6TREN and gambogic acid) showed no or very poor anti-CXCR4 inhibitory activity. Thus, CXCL12 competition binding studies were proven to be highly valuable as an initial screening assay and indicative for the pharmacological and functional profile of competitive CXCR4 antagonists, which will help the design of new potent CXCR4 inhibitors.
Immunoregulatory Effects of Multipotent Adult Progenitor Cells in a Porcine Ex Vivo Lung Perfusion Model Stem Cell Research & Therapy. | Pubmed ID: 28676074 Primary graft dysfunction (PGD) is considered to be the end result of an inflammatory response targeting the new lung allograft after transplant. Previous research has indicated that MAPC cell therapy might attenuate this injury by its paracrine effects on the pro-/anti-inflammatory balance. This study aims to investigate the immunoregulatory capacities of MAPC cells in PGD when administered in the airways.
Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs Journal of Medicinal Chemistry. | Pubmed ID: 28682067 Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.
Design, Synthesis, and the Biological Evaluation of a New Series of Acyclic 1,2,3-Triazole Nucleosides Archiv Der Pharmazie. | Pubmed ID: 28763115 A new strategy for the synthesis of N-benzoylated- and N-benzylated N-propargylquinazoline-2,4-diones 30a-d and 31a-d from isatoic anhydride 41 is reported. The alkynes 30a-d and 31a-d were applied in the 1,3-dipolar cycloadditions with azides 27 and 28 to synthesize acyclic 1,2,3-triazole nucleosides. The obtained alkynes and 1,2,3-triazole were evaluated for antiviral activity against a broad range of DNA and RNA viruses. The alkyne 30d showed activity against adenovirus-2 (EC = 8.3 μM), while compounds 37a and 37d were also active toward herpes simplex virus-1 wild-type and thymidine kinase deficient (HSV-1 TK) strains (ECvalues in the range of 4.6-13.8 μM). In addition, compounds 30a, 30b, 37b, and 37c exhibited activity toward varicella-zoster virus (VZV) TKand TKstrains (EC = 2.1-9.5 μM). The compound 30b proved to be the most selective against VZV and displayed marginal activity against human cytomegalovirus (HCMV). Although the compound 30a had improved anti-HCMV activity, the increase in anti-HCMV activity was accompanied by significant toxicity. Compounds 37a and 37d showed inhibitory effects toward the human T lymphocyte (CEM) cell line (IC = 21 ± 7 and 22 ± 1 μM, respectively), while compound 35 exhibited cytostatic activity toward HMEC-1 cells (IC = 28 ± 2 μM).
Signaling Properties of the Human Chemokine Receptors CXCR4 and CXCR7 by Cellular Electric Impedance Measurements PloS One. | Pubmed ID: 28945785 The chemokine receptor 4 (CXCR4) and 7 (CXCR7) are G-protein-coupled receptors involved in various diseases including human cancer. As such, they have become important targets for therapeutic intervention. Cell-based receptor assays, able to detect agents that modulate receptor activity, are of key importance for drug discovery. We evaluated the potential of cellular electric impedance for this purpose. Dose-dependent and specific stimulation of CXCR4 was detected upon addition of its unique chemokine ligand CXCL12. The response magnitude correlated with the CXCR4 expression level. Gαi coupling and signaling contributed extensively to the impedance response, whereas Gαq- and Gβγ-related events had only minor effects on the impedance profile. CXCR7 signaling could not be detected using impedance measurements. However, increasing levels of CXCR7 expression significantly reduced the CXCR4-mediated impedance readout, suggesting a regulatory role for CXCR7 on CXCR4-mediated signaling. Taken together, cellular electric impedance spectroscopy can represent a valuable alternative pharmacological cell-based assay for the identification of molecules targeting CXCR4, but not for CXCR7 in the absence of CXCR4.
Aminomethylation of Heliomycin: Preparation and Anticancer Characterization of the First Series of Semi-synthetic Derivatives European Journal of Medicinal Chemistry. | Pubmed ID: 29137865 A series of 4-aminomethyl derivatives of heliomycin 1 was prepared using the Mannich reaction. The modification significantly improved aqueous solubility of the initially poorly soluble antibiotic. Testing the antiproliferative efficacy revealed a potent activity of heliomycin as well as its new derivatives on a panel of mammalian tumor cells including drug resistant variants. In contrast to 1 the new derivatives 7a, 7l, 7p generated a high level of ROS associated with induction of apoptosis in T24 bladder cancer cells. Introduction of 4-aminomethyl moiety increased the affinity to DNA and the ability to inhibit topoisomerase 1 making 7p the most promising candidate for further preclinical evaluation. Thus, aminomethylation is the first-in-class successful transformation of the antibiotic 1 resulting in an improved water solubility of derivatives and promising properties in search of novel anticancer drug candidates.
Chloro-1,4-dimethyl-9H-carbazole Derivatives Displaying Anti-HIV Activity Molecules (Basel, Switzerland). | Pubmed ID: 29385738 Despite the progress achieved by anti-retroviral drug research in the last decades, the discovery of novel compounds endowed with selective antiviral activity and reduced side effects is still a necessity. At present, the most urgent requirement includes the improvement of HIV (Human Immunodeficiency Virus) prevention and sexual transmission and the development of new drugs to treat the chronic lifelong infection.
A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity PLoS Pathogens. 2013 | Pubmed ID: 23935482 Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4⁺ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).


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2. I went outside once
3. Animal kingdom
4. Painful truth Art illustration sketch drawing
6. Happy Duckling!
7. I bet their mixtape is fire
8. Cats and Ice ball
9. Like brother
10. How would you name this beautiful dog
11. Damn ninjas cutting onions again
12. Rachel Vallori
13. Birthday Cake for my boyfriend
14. Found this beauty in the laundry shop
15. This is deep *mom joke*
16. Lilymaymac
17. Cute face
18. Adorable animals hugging
19. I like the bonus
20. Are u serious
21. When Team Instinct takes a gym
22. Stroll in the park
23. Still think faceswaps are fun?
24. A little tip from Cassidy (Preacher) to all our vegetarian friends!
25. Image of the pollution caused by Japan
26. Das ist gar kein Fussballspiel
27. Fast and Furious : armored edition
28. No touchy fishy
29. Rick being Rick
30. Hooman I bwought fou a fupper
31. When my wife driving
32. I wonder how many hours that took
33. Meet Graham: The Only Person Designed To Survive On Our Roads
34. This is how magikarp ran away from you
35. Friend has a library
36. A normal dog would have looked guilt
37. Closeup of a puffin with a mouthful of sand eels
38. What do these 18 pictures have in common?
39. These Mirror Marble Cakes By Russian Confectioner Are Just Too Perfect on 9GAG
40. The hype is real!!

subset: commoncrawl


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Swimsuit Cover-up
I had a little of the flower print fabric left over from my
, so I decided to whip up a swimsuit cover-up for our trip to Cancun.
For this look you will need:
1 1/2 yards of fabric (I used a printed jersey fabric that was light and dries quickly)
thread (this is usually kept right next to the regular thread in craft stores)
2 bobbins (one for normal thread, one for elastic thread)
spray bottle
I used the shirring technique for the top part of the dress, that might look a little crazy, but is actually really easy once you get the hang of it.
First I started with 2 pieces of fabric that measured 26" wide and 29 1/2" long (you can adjust these sizes to be as long or as short as you want). You want the total width of the fabric to be about 1 1/2 times the measurement of your bust. This will allow for a nice stretch at the top.
Using normal thread, sew the 2 long sides together with 1/2" seam on both sides (remember to have the right sides facing each other) .
Then, finish off the top of the dress by turning the fabric down 1/4", then turn in down another 1/4" to give it a clean edge.
Now is where your elastic thread comes into play. Grab a fresh bobbin and wrap the elastic thread around it by hand. Don't pull too tight, but keep a little tension. This part went a lot faster than I thought, less than a minute.
I'll let
Ruffles and Stuff
take it from here. She gives an excellent
shirring tutorial
on her blog.
Here are a few pictures of my progress:
Once you're done sewing the rows with the elastic thread you're almost done. I ended up having 12 rows about 3/4" apart. To be totally honest, I just eyeballed most of the lines as I sewed them rather than draw them on the fabric. Shirring is
forgivable, so don't be afraid if your lines aren't perfectly straight. Mine were crooked for shizzle.
Then just spritz the top section with some water and hold a semi hot iron on the fabric for a few seconds at a time. This will dry the fabric and tighten up the elastic.
Now, all you have left is the hem. Fold it under 1/2" twice, and you're all set!
I had a little leftover fabric from the purple shirt I used in the lavender dress (I never throw away my scraps, they always come in handy). So I cut up some strips, and braided them together:
(please excuse the ghetto-fabulous way that I pinned the strips to a chair cushion)
Then I just hand stitched it to the top of the dress to add a little character.
This dress came in very handy along the beaches of Cancun.


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Consumers could be facing severe debt management issues if they use too much plastic this Christmas, it has been advised.
The warning not to over-spend has come from the Finance & Leasing Association and the Consumer Credit Counselling Service, which noted that Christmas is a time when a lack of restraint can cause financial problems.
Last year saw 11 per cent more being spent on
They suggested that one solution is to avoid splashing out on credit, while those who do so should shop around for the cheapest deal before splashing out.
Britons will spend 35 per cent less on presents this Christmas than they did ten years ago, according to research published by Saga last week.
Its study found that the average amount dedicated to gifts will be £435, whereas the amount spent per person in 1999 would be £666 in today's money.


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I have been a member of Etsy Metal for quite a few years now and I am now co-curating the Etsy Metal Charm Swap again with Laney Clark of Silent Goddess. This is the 14th charm swap (CS14). Laney and I curated Etsy Metal Charm Swap 9 together and had a great time! The charm swaps work like this: we have a sign up sheet of 20 Etsy Metal members. Each member has roughly 6 mos to make 22 charms... 1 charm is for each of the 20 participants, 1 is to sell in the team shop, and 1 is to be hung on a bracelet that is sold in the team shop and consists of one charm from each participant. Once the charms are made they are shipped to one of the curators who divide them up and ship them back to each of the participants. You can see some of my charms from past swaps below. Check out the team shop to see and purchase items from past swaps and to see more of my jewelry you can check out my shop.
mini constricted heart charm CS7
mixed metal charm CS8
sunburst charm CS9
patchwork charm CS10
mixed metal eclipse charm CS11
mixed metal rose charm CS12
Lucky # 13 charm CS13


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Tensions Rise on the Tapajos River
Peaceful Mundurukú gathering met with brutality
- May 19, 2014
- Christian Poirier
"For us everything is sacred: The river, earth, wind, fire, and the forest...when the government says it will do something on our land, it hurts our heart because we are all a part of it."Kabaiwun Kaba
Justice Now!
Join the worldwide chorus calling for justice by urging Brazil's Supreme Court to rule on lawsuits against the Belo Monte Dam!
As the Brazilian government ramps up reckless plans to build another mega-dam complex – this time on the Amazon's Tapajos River – tensions reached a fever pitch last week with a hate-driven mob raining violence on a peaceful protest gathering of Mundurukú people. This brutal attack, meant to terrorize an indigenous group that has resolutely opposed the government's attacks on their lands and river, is a shameful continuation of a campaign to demoralize Mundurukú resistance. It is also a renewed sign of an alarmingly racist and reactionary anti-indigenous movement in today's Brazil, reaching from the grassroots to the federal government.
After days of demonstrations in the riverside town of Jacareacanga, where hundreds of Mundurukú demanded the reinstatement of 70 indigenous professors who were arbitrary fired leaving many communities without teachers, a small group was preparing to return to their villages. As they ate breakfast they were surprised by an angry horde of over 500 townspeople made up of miners, businesspeople, and local politicians, who bombarded the Mundurukú group – which included women and young children – with rocks, explosive rockets, and gas bombs. The attack injured two young leaders and terrorized the local indigenous community.
Reports from the scene confirm that local police were present but did nothing to prevent the anti-indigenous violence, which appears to have been instigated by the town's economic and political leadership. The deputy mayor of Jacareacanga was identified among the mob alongside the local secretary of Indigenous Affairs, Ivan Alencar, who was believed to have sparked this hateful and premeditated assault. Joining a group of wildcat miners who were expelled from Mundurukú territory earlier this year, Mr. Alencar was seen shouting that the Mundurukú aim to strip the rights of townspeople.
A series of recent indigenous assemblies among the Mundurukú nation reinvigorated calls for dialogue with key leaders in Brazil's Dilma Rousseff government. Known for paralyzing the construction of the notorious Belo Monte dam with a daring and determined occupation in 2013, the Mundurukú have long maintained that the government has scorned their right to consultation, forcing them to take direct action to demand the halt of dam planning on the Tapajos River.
"The government claims that we do not want dialogue, so we determined that we must arrange this dialogue and consultations, not the government," said Kabaiwun Kaba, a member of the Mundurukú Ipereg Ayu Movement. "The government must come to our territory, to our villages, to listen to our concerns. We should not need to have to go after the government."
Brazil's systematic violation of the indigenous right to be consulted over development decisions that affect their lands and livelihoods, as enshrined in the Brazilian constitution and International Labor Organization Convention 169, is playing out on the Tapajos much like it did on the Xingu River, where Belo Monte is currently under construction. Having witnessed the disaster befalling the Xingu and its peoples, the Mundurukú are fighting to preserve their riverine home from the same fate. Meanwhile, pressure is mounting to bring massive industrial mining operations onto Mundurukú lands.
According to Kabaiwun Kaba, the Mundurukú are determined to fight new mining concessions and hydroelectric projects planned for the Tapajós, putting the group on a collision course with Brazil's most powerful political and economic interests.
"For us everything is sacred," said Kaba. "The river, earth, wind, fire, and the forest. Everything is sacred. So when the government says it will do something on our land, it hurts our heart because we are all a part of it."
The steadfast and unified resistance of the Mundurukú nation, one of Brazil's most populous, could halt the ruthless march to industrialize the Tapajos basin. This has led the government to mount a brutal intimidation campaign with constant military incursions into Mundurukú territory, purportedly to provide security for teams gathering data needed to approve the Tapajos Complex, a series of seven large dams planned for the last major undammed tributary of the Amazon. Official documents show that the Complex will flood nearly 800 km² of forest, including indigenous villages, nearly doubling the direct impacts of the Belo Monte dam.
Like Brazil's diverse indigenous communities spread across the country, Mundurukú territory contains vast and largely untapped resources, such as the hydroelectric potential of the Tapajos and its tributaries, and a wealth of metals and minerals. While Brazil's Congress works to dismantle hard-fought indigenous land rights to open up these protected territories to uncontrolled exploitation, local hate mongers work to incite intimidation and violence against indigenous communities.
Painting indigenous communities as lazy recipients of handouts and impediments to Brazil's progress, an incendiary and racist discourse reckons a return to the colonial mindset that decimated indigenous peoples across the Americas. The longstanding oppression of Brazil's Guaraní Kaiowá over sugar production on their ancestral lands is the most glaring example of these tendencies, while explosive mob violence against the Tenharim community in Amazonas State confirms the spread of this malignant movement.
The Mundurukú show no sign of waning their resistance and their commitment to defend the Tapajos, in spite of this escalating regime of terror. But with every passing day the stakes rise in this tumultuous corner of the Amazon, urgently calling on Brazilian and international civil society to stand with these threatened peoples to demand respect for their rights and protection for their lands.
Read a letter from Mundurukú leadership to the Brazilian government and people.
Translation support from Lonny Ivan Meyer and Lucy Howard