- Radioiodinated progesterone derivative for progesterone receptor targeting with enhanced nucleus uptake via phenylboronic acid conjugation
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A novel 131I-radiolabeled probe with aromatic boronate motif (131I-EIPBA) was designed to target progesterone receptor (PR)–positive breast cancer with enhanced nucleus uptake. Acetylene progesterone was conjugated with pegylated phe
- Gao, Fei,Peng, Chenyu,Li, Jindian,Zhuang, Rongqiang,Guo, Zhide,Xu, Duo,Su, Xinhui,Zhang, Xianzhong
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Read Online
- Neutralization of Pathogenic Fungi with Small-Molecule Immunotherapeutics
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Systemic fungal infections represent an important public health concern, and new antifungal agents are highly desirable. Herein, we describe the design, synthesis, and biological evaluation of a novel class of antifungal compounds called antibody-recruiting molecules targeting fungi (ARM-Fs). Our approach relies on the use of non-peptidic small molecules, which selectively bind fungal cells and recruit endogenous antibodies to their surfaces, resulting in immune-mediated clearance. Using the opportunistic fungal pathogen Candida albicans as a model, we identified a highly specific bifunctional molecule able to mediate the engulfment and phagocytosis of C. albicans cells by human immune cells in biologically relevant functional assays. This work represents a novel therapeutic approach to treating fungal illness with significant potential to complement and/or combine with existing treatment strategies.
- Chirkin, Egor,Muthusamy, Viswanathan,Mann, Paul,Roemer, Terry,Nantermet, Philippe G.,Spiegel, David A.
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Read Online
- Alternative reagents for methotrexate as immobilizing anchor moieties in the optimization of MASPIT: Synthesis and biological evaluation
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We report the evaluation of two alternative chemical dimerizer approaches aimed at increasing the sensitivity of MASPIT, a three-hybrid system that enables small-molecule target protein profiling in intact human cells. To circumvent the potential limitati
- De Clercq, Dries J.H.,Risseeuw, Martijn D.P.,Karalic, Izet,De Smet, Anne-Sophie,Defever, Dieter,Tavernier, Jan,Lievens, Sam,Van Calenbergh, Serge
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Read Online
- Surface plasmon resonance study of protein-carbohydrate interactions using biotinylated sialosides
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Lectins are carbohydrate binding proteins found in plants, animals, and microorganisms. They serve as important models for understanding protein-carbohydrate interactions at the molecular level. We report here the fabrication of a novel sensing interface
- Linman, Matthew J.,Taylor, Joseph D.,Yu, Hai,Chen, Xi,Cheng, Quan
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Read Online
- Discovery of novel potent covalent inhibitor-based EGFR degrader with excellent in vivo efficacy
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Although several Epidermal growth factor receptor (EGFR) inhibitors have been approved for the treatment of non-small-cell lung cancers (NSCLC), acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology Proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Here, we reported the discovery of Dacomitinib-based EGFR degraders. Promising compound 13 can effectively induce degradation of EGFRdel19 with DC50 value of 3.57 nM in HCC-827 cells, but not to other EGFR mutant, wild-type EGFR protein and the same family receptors (HER2 and HER4). Of note, 13 is the first EGFR-PROTAC to evaluate antitumor effect in vivo, and exhibited excellent antitumor efficacy (TGI = 90%) at a dose of 30 mg/kg without causing observable toxic effects. The preliminary mechanism study demonstrated that 13 can efficiently induce EGFR protein degradation through ubiquitin proteasome pathway and inhibit phosphorylation of downstream pathways in vitro and in vivo, which indicated that 13 exerted antitumor effect by degradation of EGFR protein in tumor tissue. Overall, our study provided further evidence to validate EGFR-PROTACs as a promising strategy for lung cancer therapy.
- Cui, Jiaqi,Du, Yu,Huang, Lei,Niu, Jing,Shi, Shi,Xu, Yungen,Zhu, Qihua
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supporting information
(2022/01/26)
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- HETEROBIFUNCTIONAL MOLECULES AS TEAD INHIBITORS
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The invention relates to compounds and methods of using said compounds, as well as pharmaceutical compositions containing such compounds, for treating diseases and conditions mediated by TEAD, such as cancer.
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Paragraph 0259-0260; 0355-0356; 0456-0457; 0492-0493
(2021/09/11)
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- COMPOSITIONS AND METHODS RELATED TO MOLECULAR CONJUGATION
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The invention relates to activated Michael acceptor (AMA) compounds that can undergo conjugation with biomolecules containing Michael donor moieties, thereby providing plasma-stable antibody-drug conjugates (ADCs). Pharmaceutical compositions of the ADCs are disclosed as well. Also provided herein are a number of applications (e.g., therapeutic applications) in which the compositions are useful.
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Page/Page column 49; 50
(2021/06/11)
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- Supramolecular compound nano-carrier as well as preparation method and application thereof
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The invention discloses a supramolecular compound nano-carrier as well as a preparation method and application thereof, and relates to the technical field of polymer chemistry and biological detection engineering. According to the supramolecular compound nano-carrier disclosed by the invention, a two-dimensional nanosheet supramolecular structure system generated by self-assembly is driven by an anion induction effect, and a supramolecular compound nano-carrier is of a single-layer nanosheet supramolecular structure constructed by a highly-oriented one-dimensional nanorod. A hydrophobic perylene group part is used as a skeleton part for constructing the highly-oriented one-dimensional nanorod, and the charge density of a single-layer nanosheet can be regulated and controlled. The surface of the water-soluble multivalent hydrophilic part can be loaded with DNAzyme deoxyribozyme for specific detection of heavy metal ions through electrostatic interaction, and the water-soluble multivalent supramolecular compound nano sensor is constructed. Based on a fluorescence change mechanism caused by specific cutting of heavy metal ions, The fluorescence detection of the heavy metal ions in food and biological tissues is realized, and the detection effect of the heavy metal ions is greatly enhanced.
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Paragraph 0109; 0123
(2021/08/14)
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- PROTAC compound for targeted degradation of IDO1, and preparation method and application thereof
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The invention provides a PROTAC compound represented by formula I and used for targeted degradation of IDO1, and a pharmaceutically acceptable salt, a hydrate or a solvate thereof. In the formula I, Xrepresents -CH2 or -C = O, Y represents -CH2 or -C= O, and n is a natural number from 2 to 9. The PROTAC compound for targeted degradation of the IDO1 has efficient activity of targeted degradation of the IDO1 protein.
- -
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Paragraph 0024-0026; 0038-0041
(2020/06/17)
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- Vitamin-guanosine monophosphate conjugates for: In vitro transcription priming
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Expanding the catalytic repertoire of ribozymes to include vitamin synthesis requires efficient labelling of RNA with the substrate of interest, prior to in vitro selection. For this purpose, we rationally designed and synthesized six GMP-conjugates carry
- Bande, Omprakash,Groaz, Elisabetta,Herdewijn, Piet,Marlière, Philippe,Papastavrou, Nikolaos
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supporting information
p. 2787 - 2790
(2020/03/17)
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- FUSED HETEROCYCLIC BENZODIAZEPINE DERIVATIVES AND USES THEREOF
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The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
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Page/Page column 126
(2020/05/29)
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- Targeting G Protein-Coupled Receptors with Magnetic Carbon Nanotubes: The Case of the A3 Adenosine Receptor
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The A3 adenosine receptor (AR) is a G protein-coupled receptor (GPCR) overexpressed in the membrane of specific cancer cells. Thus, the development of nanosystems targeting this receptor could be a strategy to both treat and diagnose cancer. Iron-filled carbon nanotubes (CNTs) are an optimal platform for theranostic purposes, and the use of a magnetic field can be exploited for cancer magnetic cell sorting and thermal therapy. In this work, we have conjugated an A3AR ligand on the surface of iron-filled CNTs with the aim of targeting cells overexpressing A3ARs. In particular, two conjugates bearing PEG linkers of different length were designed. A docking analysis of A3AR showed that neither CNT nor linker interferes with ligand binding to the receptor; this was confirmed by in vitro preliminary radioligand competition assays on A3AR. Encouraged by this result, magnetic cell sorting was applied to a mixture of cells overexpressing or not the A3AR in which our compound displayed indiscriminate binding to all cells. Despite this, it is the first time that a GPCR ligand has been anchored to a magnetic nanosystem, thus it opens the door to new applications for cancer treatment.
- Pineux, Florent,Federico, Stephanie,Klotz, Karl-Norbert,Kachler, Sonja,Michiels, Carine,Sturlese, Mattia,Prato, Maurizio,Spalluto, Giampiero,Moro, Stefano,Bonifazi, Davide
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p. 1909 - 1920
(2020/09/11)
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- Erratum: Efficient Targeted Degradation via Reversible and Irreversible Covalent PROTACs (Journal American Chemical Society (2020) DOI: 10.1021/jacs.9b13907)
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This addition corrects several errors in the chemical drawings in the article. The correction has no influence on the data or conclusions of the work. The configuration of the chiral carbon in Figure 1 in the main text was originally drawn as S. The corrected figure shown here depicts the R enantiomer used in this work. (Figure presented) In the Supporting Information PDF files, the configuration of the chiral carbon of the BTK binder in supplementary Table 1 (page S9), supplementary Figure 4 (page S13), and several of the synthetic schemes (pages S17-S42) was originally drawn and marked as S by error. The corrected supplementary file depicts the R enantiomer, which was the sole enantiomer used in the work. The linker in the right panel of supplementary Table 1 (page S9) was missing two carbons in the drawing, and the linker size written for compound PG15 (RC-0b) in the table was incorrect. The corrected supplementary file contains the correct drawings and linker sizes.
- Aharoni, Hila,Albeck, Shira,Avram, Liat,Brandis, Alexander,Gabizon, Ronen,Gehrtz, Paul,Gurwicz, Neta,Herishanu, Yair,Katz, Ben-Zion,Livnah, Ella,London, Nir,Shorer, Yamit,Shraga, Amit,Shulman, Ziv,Unger, Tamar
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supporting information
p. 11316 - 11316
(2020/07/28)
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- Efficient Targeted Degradation via Reversible and Irreversible Covalent PROTACs
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Proteolysis targeting chimeras (PROTACs) represent an exciting inhibitory modality with many advantages, including substoichiometric degradation of targets. Their scope, though, is still limited to date by the requirement for a sufficiently potent target binder. A solution that proved useful in tackling challenging targets is the use of electrophiles to allow irreversible binding to the target. However, such binding will negate the catalytic nature of PROTACs. Reversible covalent PROTACs potentially offer the best of both worlds. They possess the potency and selectivity associated with the formation of the covalent bond, while being able to dissociate and regenerate once the protein target is degraded. Using Bruton's tyrosine kinase (BTK) as a clinically relevant model system, we show efficient degradation by noncovalent, irreversible covalent, and reversible covalent PROTACs, with 85% degradation. Our data suggest that part of the degradation by our irreversible covalent PROTACs is driven by reversible binding prior to covalent bond formation, while the reversible covalent PROTACs drive degradation primarily by covalent engagement. The PROTACs showed enhanced inhibition of B cell activation compared to ibrutinib and exhibit potent degradation of BTK in patient-derived primary chronic lymphocytic leukemia cells. The most potent reversible covalent PROTAC, RC-3, exhibited enhanced selectivity toward BTK compared to noncovalent and irreversible covalent PROTACs. These compounds may pave the way for the design of covalent PROTACs for a wide variety of challenging targets.
- Gabizon, Ronen,Shraga, Amit,Gehrtz, Paul,Livnah, Ella,Shorer, Yamit,Gurwicz, Neta,Avram, Liat,Unger, Tamar,Aharoni, Hila,Albeck, Shira,Brandis, Alexander,Shulman, Ziv,Katz, Ben-Zion,Herishanu, Yair,London, Nir
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supporting information
p. 11734 - 11742
(2020/07/21)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
- -
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Paragraph 2254; 2255
(2019/07/10)
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- Control over the macrocyclisation pathway and product topology in a copper-templated catenane synthesis
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We report here that the product topology in a copper-templated catenane synthesis can be controlled by favouring a particular macrocyclisation pathway, offering an additional strategy for improving the efficiency of catenane formation. A linear [4]catenan
- Yee, Chi-Chung,Ng, Antony Wing Hung,Au-Yeung, Ho Yu
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supporting information
p. 6169 - 6172
(2019/06/07)
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- Ion Conducting ROMP Monomers Based on (Oxa)norbornenes with Pendant Imidazolium Salts Connected via Oligo(oxyethylene) Units and with Oligo(ethyleneoxy) Terminal Moieties
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A matrix of 22 two-armed norbornene-based imidazolium TFSI monomers (8) was synthesized to determine the optimal structure in terms of single ion conductivity. For the chain tethering the imidazolium ring to the norbornene ring three or four oxyethylene units are optimal. A terminal group of two ethyleneoxy units was optimal. NMR studies indicated that both the tether oxyethylene units and the terminal ethyleneoxy units interact with the imidazolium cation via hydrogen bonding. 8r (X = 4, Y = 2) exhibited a conductivity of 9.57 × 10-5 S/cm at 25 °C and a Tg of -46 °C. Low Tg values do not correlate with higher conductivity as a result of the H-bonding interactions. Stability toward autopolymerization and reasonable conductivities provide an acceptable platform for ion conducting ROMP polymers. Four one-armed norbornene-based imidazolium TFSI monomers (15) were prepared with tetra(ethyleneoxy) linkers/spacers and variable terminal groups. All of these exhibited low Tgs (10-4 S/cm, the highest being 4.39 × 10-4 S/cm for 15c (Tg = -69 °C), the analogue of 8r, providing hope for outstanding polymers. Three oxanorbornene-based two-armed imidazolium TFSI monomers (18) were prepared with varied linkers and terminal groups. 18b possesses a room temperature conductivity of 1.2 × 10-4 S/cm, again augering well for polymers derived therefrom by ROMP.
- Price, Terry L.,Choi, U Hyeok,Schoonover, Daniel V.,Arunachalam, Murugan,Xie, Renxuan,Lyle, Steven,Colby, Ralph H.,Gibson, Harry W.
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p. 1371 - 1388
(2019/02/19)
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- Medicine conjugate and method for prolonging half-life of medicine molecule
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The invention discloses a medicine conjugate and a method for prolonging half-life of a medicine molecule. The medicine conjugate is prepared through modifying the medicine molecule with a micromolecule combined with a half antigen, wherein the half antigen is the half antigen having an endogenous antibody. The half antigen molecule is modified on the medicine molecule, and the modified medicine molecule can be specifically combined with the endogenous antibody in accordance with the half antigen, so that the in vivo half-life of the medicine molecule can be notably prolonged.
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Paragraph 0061-0064; 0081-0084
(2019/11/19)
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- Expedient synthesis of trifunctional oligoethyleneglycol-amine linkers and their use in the preparation of PEG-based branched platforms
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We designed a convergent synthesis pathway that provides access to trifunctional oligoethyleneglycol-amine (OEG-amine) linkers. By applying the reductive coupling of a primary azide to bifunctional OEG-azide precursors, the corresponding symmetrical dialkylamine bearing two homo-functional end chain groups and a central nitrogen was obtained. These building blocks bear minimal structural perturbation compared to the native OEG backbone which makes them attractive for biomedical applications. The NMR investigations of the mechanism process reveal the formation of nitrile and imine intermediates which can react with the reduced free amine form. Additionally, these trifunctional OEG-amine linkers were employed in a coupling reaction to afford branched multifunctional PEG dendrons which are molecularly defined. These discrete PEG-based dendrons (n = 16, 18 and 36) could be useful for numerous applications where multivalency is required.
- Ursuegui, Sylvain,Schneider, Jérémy P.,Imbs, Claire,Lauvoisard, Florian,Dudek, Marta,Mosser, Michel,Wagner, Alain
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supporting information
p. 8579 - 8584
(2019/01/07)
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- Exploring Rigid and Flexible Core Trivalent Sialosides for Influenza Virus Inhibition
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Herein, the chemical synthesis and binding analysis of functionalizable rigid and flexible core trivalent sialosides bearing oligoethylene glycol (OEG) spacers interacting with spike proteins of influenza A virus (IAV) X31 is described. Although the flexible Tris-based trivalent sialosides achieved micromolar binding constants, a trivalent binder based on a rigid adamantane core dominated flexible tripodal compounds with micromolar binding and hemagglutination inhibition constants. Simulation studies indicated increased conformational penalties for long OEG spacers. Using a systematic approach with molecular modeling and simulations as well as biophysical analysis, these findings emphasize on the importance of the scaffold rigidity and the challenges associated with the spacer length optimization.
- Kiran, Pallavi,Bhatia, Sumati,Lauster, Daniel,Aleksi?, Stevan,Fleck, Carsten,Peric, Natalija,Maison, Wolfgang,Liese, Susanne,Keller, Bettina G.,Herrmann, Andreas,Haag, Rainer
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supporting information
p. 19373 - 19385
(2018/11/27)
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- BIFUNCTIONAL ANTIFUNGAL AGENTS AND METHODS OF TREATING FUNGAL INFECTION
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The present invention is directed to bifunctional compounds which are useful in the treatment of fungal infections. The present compounds contains at least one fungal binding moiety (FBM) which is linked to at least one antibody binding moiety (ΑB/s
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Page/Page column 44, 46-47
(2018/03/09)
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- HDAC INHIBITORS-BASED ANTIBODY DRUG CONJUGATES (ADCs) AND USE IN THERAPY
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The present invention relates to novel Histone Deacetylase Inhibitors (HDACi)- based antibody drug conjugates particularly with antibodies directed to ErbB1, ErbB2 and ErbB3 receptors, pharmaceutical compositions comprising said antibodies as well as to their use in the treatment of cancer or tumor and other diseases where a modulation of one or more histone deacetylase isoforms can be effective for therapeutic interventions.
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Paragraph 71; 72
(2018/10/25)
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- EXENATIDE MODIFIER AND USE THEREOF
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Disclosed are an exenatide modifier for connecting the exenatide to a fatty chain with a carboxy in the terminus thereof by means of a hydrophilic connecting arm, and a use thereof in preparing drugs serving as a GLP-1 receptor agonist; a use in preparing drugs for preventing and/or treating diseases and/or symptoms associated with a low GLP-1 receptor activity; a use in preparing drugs for diseases and/or symptoms associated with glycometabolism; a use in preparing drugs for diabetes; a use in preparing drugs for fatty liver disease, and a use in preparing drugs for losing weight.
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Paragraph 0100
(2018/05/24)
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- Intracellular Protein-Labeling Probes for Multicolor Single-Molecule Imaging of Immune Receptor-Adaptor Molecular Dynamics
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Single-molecule imaging (SMI) has been widely utilized to investigate biomolecular dynamics and protein-protein interactions in living cells. However, multicolor SMI of intracellular proteins is challenging because of high background signals and other lim
- Sato, Ryota,Kozuka, Jun,Ueda, Masahiro,Mishima, Reiko,Kumagai, Yutaro,Yoshimura, Akimasa,Minoshima, Masafumi,Mizukami, Shin,Kikuchi, Kazuya
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supporting information
p. 17397 - 17404
(2017/12/15)
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- CONJUGATES COMPRISING SELF-IMMOLATIVE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self- immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 63; 64
(2017/06/27)
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- CONJUGATES COMPRISING PEPTIDE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and at least two active agents. In preferred embodiments, the linker comprises a peptide sequence of a plurality of amino acids, and at least two of the active agents are covalently coupled to side chains of the amino acids. The antibody-drug conjugate may comprise a self-immolative group, preferably two-self-immolative groups. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 74
(2017/08/08)
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- LINKER MOLECULE FOR MULTIPLEX RECOGNITION BY ATOMIC FORCE MICROSCOPY (AFM)
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Some of the embodiments of the present disclosure relate to a compound of the formula, and methods of preparing and using same.
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Paragraph 0023; 0024; 0025
(2017/06/12)
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- SILICON BASED DRUG CONJUGATES AND METHODS OF USING SAME
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Described herein are silicon based conjugates capable of delivering one or more payload moieties to a target cell or tissue. Contemplated conjugates may include a silicon-heteroatom core, one or more optional catalytic moieties, a targeting moiety that permits accumulation of the conjugate within a target cell or tissue, one or more payload moieties (e.g., a therapeutic agent or imaging agent), and two or more non-interfering moieties covalently bound to the silicon-heteroatom core.
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Paragraph 0702; 0723; 0724
(2017/08/07)
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- SILANOL BASED THERAPEUTIC PAYLOADS
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Described herein in part are silanol based therapeutic payloads comprising a silanol terminus, a divalent spacer moiety, and a drug moiety capable of effecting a target cell or tissue.
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Paragraph 00161
(2018/01/17)
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- Towards potential nanoparticle contrast agents: Synthesis of new functionalized PEG bisphosphonates
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The use of nanotechnologies for biomedical applications took a real development during these last years. To allow an effective targeting for biomedical imaging applications, the adsorption of plasmatic proteins on the surface of nanoparticles must be prevented to reduce the hepatic capture and increase the plasmatic time life. In biologic media, metal oxide nanoparticles are not stable and must be coated by biocompatible organic ligands. The use of phosphonate ligands to modify the nanoparticle surface drew a lot of attention in the last years for the design of highly functional hybrid materials. Here, we report a methodology to synthesize bisphosphonates having functionalized PEG side chains with different lengths. The key step is a procedure developed in our laboratory to introduce the bisphosphonate from acyl chloride and tris(trimethylsilyl)phosphite in one step.
- Kachbi-Khelfallah, Souad,Monteil, Maelle,Cortes-Clerget, Margery,Migianu-Griffoni, Evelyne,Pirat, Jean-Luc,Gager, Olivier,Deschamp, Julia,Lecouvey, Marc
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supporting information
p. 1366 - 1370
(2016/08/02)
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- MACROCYCLIC PEPTIDES USEFUL AS IMMUNOMODULATORS
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The present disclosure provides compounds which are immunomodulators and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.
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Page/Page column 472; 473
(2016/06/06)
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- COMPOUNDS FOR THE MODULATION OF MYC ACTIVITY
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The present invention provides novel compounds of Formula (I) and Formula (II) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases, e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angio genesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases in a subject.
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Paragraph 1061
(2017/01/31)
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- Compounds with higher PKG (protein kinase G) inhibitory activity and preparation method of compounds
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The invention discloses compounds which have higher PKG (protein kinase G) inhibitory activity and are represented as a formula I, pharmaceutically acceptable salts, pharmaceutical composition containing the novel compounds, as well as an application of the novel compounds in treatment of pain, especially chronic pain. The invention further discloses a preparation method of the compounds and new intermediates. R1 and R2 are the same or different and are selected from a group comprising halogen (such as F or Cl), C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R3 is a terminal group and is selected from a group comprising H, halogen, alkyl, naphthenic base, alkenyl, alkynyl, aryl and heteroaryl; n is the number of repetitive units and is an integer in a range from 1 to 15.
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Paragraph 0262; 0263; 0264
(2016/10/08)
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- COMPOUND HAVING HIGHER INHIBITION OF PROTEIN KINASE G ACTIVITY AND PREPARATION METHOD THEREFOR
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Disclosed are a compound of Formula I having higher inhibition of protein kinase G (PKG) activity and pharmaceutically acceptable salts thereof. In Formula I, R1 and R2 are the same or different, each being independently chosen from the halogens, the C1-C6 alkoxyl group, the C1-C6 alkyl group, the C2-C6 alkenyl group, and the C2-C6 alkynyl group; R3 is chosen from H, the halogens, the substituted or unsubstituted C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, and C2-C6 alkynyl group, aryl group, and heteroaryl group; and n is an integer between 0 and 15. Also disclosed is a pharmaceutical composition comprising said compound, the use of the compound in treating pains, in particular chronic pain, a preparation method for the compound, and a new intermediate.
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Paragraph 0111; 0112
(2016/12/12)
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- Candidate PET Radioligand Development for Neurofibrillary Tangles: Two Distinct Radioligand Binding Sites Identified in Postmortem Alzheimer's Disease Brain
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[18F]THK-523 and [18F]807 are promising radioligands for imaging neurofibrillary tangles (NFTs) with positron emission tomography (PET) in neurodegenerative diseases, such as Alzheimer's disease (AD) and traumatic brain injury. Although [18F]THK-523 and [18F]T807 are considered high-affinity selective radioligands for NFTs, uncertainty has existed as to whether PET radioligands for imaging NFTs bind to the same molecular site because in vitro assays for ligands binding to NFTs have been lacking. We labeled THK-523 and T807 with tritium to serve as reference radioligands for in vitro binding assays with AD brain homogenates for newly synthesized ligands. With these radioligands, we identified two distinct binding sites for small molecules, one site with high affinity for THK-523 and the other with high affinity for T807. Moreover, binding assays with [3H]PIB confirmed that the two newly identified binding sites are also distinct from the thioflavin-T binding site where all current clinically useful PET radioligands for imaging β-amyloid plaque bind with high affinity. The two newly identified binding sites are considered to reside on NFTs rather than on β-amyloid plaques. Furthermore, we applied all three binding assays to a set of newly prepared compounds, based on chain modifications to THK-523. Some compounds with high affinity and selectivity for the THK-523 binding site emerged from this set, including one with amenability to labeling with fluorine-18, namely, ligand 10b.
- Cai, Lisheng,Qu, Baoxi,Hurtle, Bryan T.,Dadiboyena, Sureshbabu,Diaz-Arrastia, Ramon,Pike, Victor W.
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p. 897 - 911
(2016/08/02)
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- Solid-Phase-Based Synthesis of Ureidopyrimidinone-Peptide Conjugates for Supramolecular Biomaterials
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Supramolecular polymers have shown to be powerful scaffolds for tissue engineering applications. Supramolecular biomaterials functionalized with ureidopyrimidinone (UPy) moieties, which dimerize via quadruple hydrogen-bond formation, are eminently suitable for this purpose. The conjugation of the UPy moiety to biologically active peptides ensures adequate integration into the supramolecular UPy polymer matrix. The structural complexity of UPy-peptide conjugates makes their synthesis challenging and until recently low yielding, thus restricted the access to structurally diverse derivatives. Here we report optimization studies of a convergent solid-phase based synthesis of UPy-modified peptides. The peptide moiety is synthesized using standard Fmoc solid-phase synthesis and the UPy fragment is introduced on the solid-phase simplifying the synthesis and purification of the final UPy-peptide conjugate. The convergent nature of the synthesis reduces the number of synthetic steps in the longest linear sequence compared to other synthetic approaches. We demonstrate the utility of the optimized route by synthesizing a diverse range of biologically active UPy-peptide bioconjugates in multimilligram scale for diverse biomaterial applications. 1 Introduction 2 Divergent Synthesis 3 Convergent Synthesis 4 UPy-Amine Strategy 5 UPy-Carboxylic Acid Strategy 6 Conclusion.
- De Feijter, Isja,Goor, Olga J. G. M.,Hendrikse, Simone I. S.,Comellas-Aragonès, Marta,S?ntjens, Serge H. M.,Zaccaria, Sabrina,Fransen, Peter P. K. H.,Peeters, Joris W.,Milroy, Lech-Gustav,Dankers, Patricia Y. W.
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supporting information
p. 2707 - 2713
(2015/11/27)
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- BCR-ABL TYROSINE-KINASE LIGANDS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME
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Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. invivo) to form a multimer (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding sites on a Bcr-Abl tyrosine kinase.
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Paragraph 00461; 00478; 00479
(2015/07/23)
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- TUNABLE PHENYLACETYLENE HOSTS
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A compound, or a salt thereof, having the formula wherein Y is n is 1 or 2; each R is independently H, alkyl, substituted alkyl, a polyether moiety, carboxyl, substituted carboxyl, carbamate, substituted carbonate, carbonyloxy, alkoxy, substituted alkoxy,
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Paragraph 0282
(2014/02/16)
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- 1,8-Dioxyanthracene-Derived Crown Ethers: Synthesis, Complexation with Paraquat and Assembly of a Tetracationic Cyclophane-Crown Ether Based [2]Catenane
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1,8-Dioxyanthracene-based bisarylene crown ethers, composed of ethylene glycol chains and aromatic moieties, have been synthesized. Complexation studies revealed that these crown ethers could form 1:1 complexes with methyl viologen dication (N,N′-dimethyl
- Tang, Bo,Yang, Hong-Mei,Hu, Wen-Jing,Ma, Ming-Liang,Liu, Yahu A.,Li, Jiu-Sheng,Jiang, Biao,Wen, Ke
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p. 6925 - 6934
(2016/02/19)
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- Protein and enzyme gated supramolecular disassembly
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An amphiphilic nanoassembly was designed to respond to the concurrent presence of a protein and an enzyme. We present herein a system, where in the presence of these two stimuli supramolecular disassembly and molecular release occur. This molecular releas
- Guo, Jing,Zhuang, Jiaming,Wang, Feng,Raghupathi, Krishna R.,Thayumanavan
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supporting information
p. 2220 - 2223
(2014/03/21)
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- Solid phase synthesis of functionalised SAM-forming alkanethiol- oligoethyleneglycols
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We present an efficient solid phase synthesis methodology that provides easy access to a range of functionalised long-chain alkanethiol- oligoethyleneglycols that form well-defined self-assembled monolayers on gold and are compatible with pre- or post-ass
- Murray, James,Nowak, Dominika,Pukenas, Laurynas,Azhar, Rizuan,Guillorit, Mathieu,Waelti, Christoph,Critchley, Kevin,Johnson, Steven,Bon, Robin S.
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p. 3741 - 3744
(2014/06/10)
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- In vitro evolution of a Friedel-Crafts deoxyribozyme
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We report the in vitro selection of a single-stranded 72-nucleotide DNA enzyme (deoxyribozyme) that catalyzes a Friedel-Crafts reaction between an indole and acyl imidazole in good yield and in aqueous solvent. Appreciable Friedel-Crafts product requires addition of copper nitrate and the deoxyribozyme. We observe deoxyribozyme-mediated bond formation for both in cis and in trans Friedel-Crafts reactions.
- Mohan, Utpal,Burai, Ritwik,McNaughton, Brian R.
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supporting information
p. 2241 - 2244
(2013/05/08)
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- Extension into the entrance channel of HIV-1 reverse transcriptase - Crystallography and enhanced solubility
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Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that feature extension into the entrance channel near Glu138. Complexes of the parent anilinylpyrimidine 1 and the morpholinoethoxy analog 2j with HIV-RT have received crystallographic characterization confirming the designs. Measurement of aqueous solubilities of 2j, 2k, the parent triazene 2a, and other NNRTIs demonstrate profound benefits for addition of the morpholinyl substituent.
- Bollini, Mariela,Frey, Kathleen M.,Cisneros, José A.,Spasov, Krasimir A.,Das, Kalyan,Bauman, Joseph D.,Arnold, Eddy,Anderson, Karen S.,Jorgensen, William L.
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p. 5209 - 5212
(2013/09/12)
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- Using an electrical potential to reversibly switch surfaces between two states for dynamically controlling cell adhesion
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Smart surfaces presenting both antifouling molecules with a charged functional group at their distal end, and molecules that are terminated by RGD peptides for cell adhesion, were fabricated and characterized (see picture). By applying potentials of +300 or -300 mV, the surfaces could be dynamically switched to make the peptide accessible or inaccessible to cells. Copyright
- Ng, Cheuk Chi Albert,Magenau, Astrid,Ngalim, Siti Hawa,Ciampi, Simone,Chockalingham, Muthukumar,Harper, Jason Brian,Gaus, Katharina,Gooding, John Justin
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supporting information; experimental part
p. 7706 - 7710
(2012/08/29)
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- Synthesis and biological characterisation of sirtuin inhibitors based on the tenovins
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The tenovins are small molecule inhibitors of the NAD+-dependent family of protein deacetylases known as the sirtuins. There remains considerable interest in inhibitors of this enzyme family due to possible applications in both cancer and neuro
- McCarthy, Anna R.,Pirrie, Lisa,Hollick, Jonathan J.,Ronseaux, Sebastien,Campbell, Johanna,Higgins, Maureen,Staples, Oliver D.,Tran, Fanny,Slawin, Alexandra M.Z.,Lain, Sonia,Westwood, Nicholas J.
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experimental part
p. 1779 - 1793
(2012/04/17)
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- New prodrugs of Adefovir and Cidofovir
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New Adefovir (PMEA) prodrugs with a pro-moiety consisting of decyl or decyloxyethyl chain bearing hydroxyl function(s), hexaethyleneglycol or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl unit were prepared starting from the tetrabutylammonium salt of the phosphonate drug and an appropriate alkyl bromide or tosylate. Analogously, two esters of Cidofovir [(S)-HPMPC] bearing a hexaethyleneglycol moiety were prepared. The activity of the prodrugs was evaluated in vitro against different virus families. A loss in the antiviral activities of the hydroxylated decyl or decyloxyethyl esters and hexaethyleneglycol esters of PMEA against human immunodeficiency virus (HIV) and herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (CMV)] occurred in comparison with the parent compound. On the other hand, the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of PMEA showed significant activities against HIV and herpesviruses. (S)-HPMPC prodrugs exhibited anti-cytomegalovirus activities in the same range as the parent drug, whereas the anti-HSV and anti-VZV activities were one- to seven-fold lower than that of Cidofovir.
- Tichy, Tomá?,Andrei, Graciela,Dra?ínsky, Martin,Holy, Antonín,Balzarini, Jan,Snoeck, Robert,Kre?merová, Marcela
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experimental part
p. 3527 - 3539
(2011/07/09)
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- Synthesis of novel fluorous surfactants for microdroplet stabilisation in fluorous oil streams
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The synthesis of a number of potential fluorous surfactants, prepared with a view to stabilising microdroplets in microfluidic systems is described. The surfactants comprised compounds with both perfluoropolyether (PFPE) and perfluoroalkyl (PFA) tails with three classes of hydrophilic head group, including crown ethers and hexaethylene glycol. Hydrophilic head groups and alkyl fluorous-based tails were coupled together via amide, ester and ether linkages to afford the fluorous surfactant candidates in good yields. The resulting molecules show promise in forming and stabilising both aqueous and non-aqueous microdroplets in fluorous oil streams within poly(dimethylsiloxane) (PDMS) devices to a greater degree than the pseudosurfactants commonly employed in microdroplet research. Crown Copyright
- Holt, Daniel J.,Payne, Richard J.,Abell, Chris
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experimental part
p. 398 - 407
(2010/04/24)
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- Supramolecular gelation of alcohol and water by synthetic amphiphilic gallic acid derivatives
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The supramolecular organogelation of alcohols was observed in relatively hydrophobic amphiphiles with a short oligo(ethylene glycol) unit and three long alkyl chains at room temperature, while the hydrogelation occurred in more hydrophilic gelators with a longer poly(ethylene glycol) unit and two long alkyl chains at various temperatures. When a hot aqueous solution of some of the synthetic hydrogelators was cooled down, the supramolecular hydrogel was formed at room temperature. In some other amphiphiles with less intermolecular interactivity in water at room temperature, a reverse phase transition of sol to gel was observed by elevating the temperature of their aqueous systems, especially below a physiological temperature, 37 °C. The supramolecular hydrogelation at a low or high temperature was dependent on a slight molecular modification of the synthetic amphiphiles.
- Tamiaki, Hitoshi,Ogawa, Keishiro,Enomoto, Keisuke,Taki, Kazutaka,Hotta, Atsushi,Toma, Kazunori
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supporting information; experimental part
p. 1661 - 1666
(2010/04/24)
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- Small and stable peptidic PEGylated quantum dots to target polyhistidine-tagged proteins with controlled stoichiometry
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The use of the semiconductor quantum dots (QD) as biolabels for both ensemble and single-molecule tracking requires the development of simple and versatile methods to target individual proteins in a controlled manner, ideally in living cells. To address t
- Dif, Aure Lien,Boulmedais, Fouzia,Pinot, Mathieu,Roullier, Victor,Baudy-Floc'h, Michele,Coquelle, Frederic M.,Clarke, Samuel,Neveu, Pierre,Vignaux, Francoise,Le Borgne, Roland,Dahan, Maxime,Gueroui, Zoher,Marchi-Artzner, Valerie
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experimental part
p. 14738 - 14746
(2010/01/06)
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- Synthesis and biological evaluation of functionalised tetrahydro-β- carboline analogues as inhibitors of Toxoplasma gondii invasion
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Techniques for the identification of the protein target(s) of small molecules are proving very important following an increase in the use of phenotype-based screening in chemical biology and drug discovery. One approach, known as the yeast-3-hybrid approach, has shown considerable potential. A key factor in the success of this approach is the preparation of a complex molecule referred to as a chemical inducer of dimerisation (CID). The synthesis of two CIDs based on a bioactive tetrahydro-β-carboline core structure is reported and evidence presented that shows the CIDs are of utility in this approach. A series of chemo- and bioinformatic studies coupled with SAR development inspired the choice of CIDs.
- Walton, Jeffrey G. A.,Patterson, Stephen,Liu, Gu,Haraldsen, Jeralyn D.,Hollick, Jonathan J.,Slawin, Alexandra M. Z.,Ward, Gary E.,Westwood, Nicholas J.
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scheme or table
p. 3049 - 3060
(2011/02/25)
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