- Regulation of Macrocycle Shuttling Rates in [2]Rotaxanes by Amino-Acid Speed Bumps in Organic–Aqueous Solvent Mixtures
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A homologous series of two-station [2]rotaxanes incorporating amino-acid units in the molecular thread has been developed. The degenerate [2]rotaxanes exhibit amino-acid specific shuttling rates between two fumaric stations related to the steric factor associated to the amino-acid side chain, as demonstrated by variable-temperature 1H NMR spectroscopy and exchange spectroscopy (EXSY). This allows tuning of the macrocycle shuttling rate over 4 orders of magnitude, which has a relatively small solvent dependency.
- Douarre, Maxime,Martí-Centelles, Vicente,McClenaghan, Nathan D.,Pianet, Isabelle,Rossy, Cybille
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- PH-regulated selectivity in supramolecular polymerizations: Switching between co- And homopolymers
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A strategy is presented to regulate the selectivity in aqueous supramolecular polymerizations by changes in pH. In neutral buffered conditions, oppositely charged phe-nylalanine-based dendritic peptide amphiphiles self-assemble into (A-B)n alternating copolymers of low polydispersity when mixed in a 1:1 comonomer feed ratio. Via pH switch of the glutamic acid and lysine side chains, attractive Coulomb interactions in the coassembled materials are screened and selective polymerization occurs to form (A)n homopolymers of the acidic comonomer at low pH and (B)n homopolymers of the basic comonomer at high pH, while the complementary comonomer is released during the transition. Reversible switching is demonstrated between these three different polymeric states, which were characterized by CD and fluorescence spectroscopy, using a peptide based minimalistic fluorophore/quencher pair, and transmission electron microscopy.
- Frisch, Hendrik,Nie, Yan,Raunser, Stefan,Besenius, Pol
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- Esterified dendritic TAM radicals with very high stability and enhanced oxygen sensitivity
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In this work, we have developed a new class of dendritic TAM radicals (TG, TdG, and dTdG) through a convergent method based on the TAM core CT-03 or its deuterated analogue dCT-03 and trifurcated Newkome-type monomer. Among these radicals, dTdG exhibits the best EPR properties with sharpest EPR singlet and highest O2 sensitivity due to deuteration of both the ester linker groups and the TAM core CT-03. Like the previous dendritic TAM radicals, these new compounds also show extremely high stability toward various reactive species owing to the dendritic encapsulation. The highly charged nature of these molecules resulting from nine carboxylate groups prevents concentration- dependent EPR line broadening at physiological pH. Furthermore, we demonstrate that these TAM radicals can be easily derivatized (e.g., PEGylation) at the nine carboxylate groups and the resulting PEGylated analogue dTdG-PEG completely inhibits the albumin binding, thereby enhancing suitability for in vivo applications. These new dendritic TAM radicals show great potential for in vivo EPR oximetric applications and provide insights on approaches to develop improved and targeted EPR oximetric probes for biomedical applications.
- Song, Yuguang,Liu, Yangping,Hemann, Craig,Villamena, Frederick A.,Zweier, Jay L.
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- Tuneable Transient Thermogels Mediated by a pH- and Redox-Regulated Supramolecular Polymerization
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A multistimuli-responsive transient supramolecular polymerization of β-sheet-encoded dendritic peptide monomers in water is presented. The amphiphiles, which contain glutamic acid and methionine, undergo a glucose oxidase catalyzed, glucose-fueled transient hydrogelation in response to an interplay of pH and oxidation stimuli, promoted by the production of reactive oxygen species (ROS). Adjusting the enzyme and glucose concentration allows tuning of the assembly and the disassembly rates of the supramolecular polymers, which dictate the stiffness and transient stability of the hydrogels. The incorporation of triethylene glycol chains introduces thermoresponsive properties to the materials. We further show that repair enzymes are able to reverse the oxidative damage in the methionine-based thioether side chains. Since ROS play an important role in signal transduction cascades, our strategy offers great potential for applications of these dynamic biomaterials in redox microenvironments.
- Spitzer, Daniel,Rodrigues, Leona Lucas,Stra?burger, David,Mezger, Markus,Besenius, Pol
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- Tuning the pH-triggered self-assembly of dendritic peptide amphiphiles using fluorinated side chains
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We report the synthesis of a series of anionic dendritic peptide amphiphiles of increasing hydrophobic character. By establishing state diagrams we describe their pH and ionic strength triggered self-assembly into supramolecular nanorods in water and highlight the impact of hydrophobic shielding in the supramolecular polymerisation process. Via the incorporation of fluorinated peptide side chains the pH-triggered monomer to polymer transition at physiological ionic strength is shifted from pH 5.0 to pH 7.4. We thereby show that compensating attractive non-covalent interactions and hydrophobic effects with repulsive electrostatic forces, a concept we refer to as frustrated growth, is a sensitive tool in order to manipulate one-dimensional supramolecular polymerisation processes in water.
- Appel, Ralph,Tacke, Sebastian,Klingauf, Jürgen,Besenius, Pol
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- Surface-Assisted Self-Assembly of a Hydrogel by Proton Diffusion
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Controlling supramolecular growth at solid surfaces is of great importance to expand the scope of supramolecular materials. A dendritic benzene-1,3,5-tricarboxamide peptide conjugate is described in which assembly can be triggered by a pH jump. Stopped-flow kinetics and mathematical modeling provide a quantitative understanding of the nucleation, elongation, and fragmentation behavior in solution. To assemble the molecule at a solid–liquid interface, we use proton diffusion from the bulk. The latter needs to be slower than the lag phase of nucleation to progressively grow a hydrogel outwards from the surface. Our method of surface-assisted self-assembly is generally applicable to other gelators, and can be used to create structured supramolecular materials.
- Spitzer, Daniel,Marichez, Vincent,Formon, Georges J. M.,Besenius, Pol,Hermans, Thomas M.
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- An improved synthesis of a trifurcated newkome-type monomer and orthogonally protected two-generation dendrons
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The one-step synthesis of amino-polyether tritert-butyl ester monomer 2, by condensation of TRIS with tert-butyl acrylate, is reported. The nitrogen of the monomer can be protected with a Cbz group; subsequent removal of the tert-butyl esters with formic
- Cardona, Claudia M.,Gawley, Robert E.
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- CELL SURFACE RECEPTOR BINDING COMPOUNDS AND CONJUGATES
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The present disclosure provides a class of compounds including a ligand moiety that specifically binds to a cell surface receptor, such as a mannose-6-phosphate receptor (M6PR) or a cell surface asialoglycoprotein receptor (ASGPR). The cell surface M6PR or ASGPR binding compounds can trigger the receptor to internalize into the cell a bound compound. The ligand moieties of this disclosure can be linked to a variety of moieties of interest without impacting the specific binding to, and function of, the cell surface receptor, e.g., M6PR or ASGPR. Also provided are compounds that are conjugates of the ligand moieties linked to a biomolecule, such as an antibody, which conjugates can harness cellular pathways to remove specific proteins of interest from the cell surface or from the extracellular milieu. Also provided are methods of using the conjugates to target a polypeptide of interest for sequestration and/or lysosomal degradation.
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Paragraph 00736
(2021/07/17)
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- GALNAC-TGFBR1 INHIBITOR CONJUGATES FOR THE TREATMENT OF LIVER DISEASES
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Conjugates comprising GalNAc moiety and a TGFβR1 inhibitor are provided. In some embodiments, the conjugates are useful for the treatment of viral infections, cancer, and fibrosis.
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Page/Page column 319-322
(2021/04/17)
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- Assessing changes in the expression levels of cell surface proteins with a turn-on fluorescent molecular probe
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Tri-nitrilotriacetic acid (NTA)-based fluorescent probes were developed and used to image His-tagged-labelled outer membrane protein C (His-OmpC) in liveEscherichia coli. One of these probes was designed to light up upon binding, which provided the means
- Hatai, Joydev,Prasad, Pragati Kishore,Lahav-Mankovski, Naama,Oppenheimer-Low, Noa,Unger, Tamar,Sirkis, Yael Fridmann,Dadosh, Tali,Motiei, Leila,Margulies, David
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supporting information
p. 1875 - 1878
(2021/03/01)
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- TARGETED PLASMA PROTEIN DEGRADATION
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The present invention is directed to the bifunctional compounds and the use of such bifunctional compounds to lower plasma levels of extracellular target molecules by lysosomal degradation. Such bifunctional compounds have a cell surface receptor ligand covalently linked to a ligand that is capable of binding to an extracellular target molecule (such as a ligand for a growth factor, a cytokine, a chemokine, a hormone, a neurotransmitter, a capsid, a soluble receptor, an extracellular secreted protein, an antibody, a lipoprotein, an exosome, a virus, a cell, or a plasma membrane protein), where the cell surface receptor is associated with receptor mediated endocytosis, including asialoglycoprotein receptor (ASGPR) mediated lysosomal degradation and mannose-6-phosphate (M6PR) mediated lysosomal degradation. Pharmaceutical compositions comprising such bifunctional compounds and methods of treating a disease or disorder mediated by an extracellular molecule using such bifunctional compounds are also provided herein.
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Page/Page column 172; 182-183
(2021/08/14)
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- GALNAC DERIVATIVES
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Modified oligonucleotides comprising a GalNAc moiety of the present disclosure along with methods of making and use, e.g., against HBV are disclosed.
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Paragraph 0136
(2019/04/11)
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- Multimerization increases tumor enrichment of peptide–photosensitizer conjugates
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Photodynamic therapy (PDT) is an established therapeutic modality for the management of cancers. Conjugation with tumor-specific small molecule ligands (e.g., short peptides or peptidomimetics) could increase the tumor targeting of PDT agents, which is ve
- Zhao, Jisi,Li, Shuang,Jin, Yingying,Wang, Jessica Yijia,Li, Wenjing,Wu, Wenjie,Hong, Zhangyong
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- Ferrichrome Has Found Its Match: Biomimetic Analogues with Diversified Activity Map Discrete Microbial Targets
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Siderophores provide an established platform for studying molecular recognition principles in biological systems. Herein, the preparation of ferrichrome (FC) biomimetic analogues varying in length and polarity of the amino acid chain separating between the tripodal scaffold and the pendent FeIII chelating hydroxamic acid groups was reported. Spectroscopic and potentiometric titrations determined their iron affinity to be within the range of efficient chelators. Microbial growth promotion and iron uptake studies were conducted on E. coli, P. putida and U. maydis. A wide range of siderophore activity was observed in the current series: from a rare case of a species-specific growth promotor in P. putida to an analogue matching FC in cross-phylum activity and uptake pathway. A fluorescent conjugate of the broad-range analogue visualized siderophore destination in bacteria (periplasmic space) vs. fungi (cytosol) mapping new therapeutic targets. Quantum dots (QDs) decorated with the most potent FC analogue provided a tool for immobilization of FC-recognizing bacteria. Bacterial clusters formed around QDs may provide a platform for their selection and concentration.
- Besserglick, Jenny,Olshvang, Evgenia,Szebesczyk, Agnieszka,Englander, Joseph,Levinson, Dana,Hadar, Yitzhak,Gumienna-Kontecka, Elzbieta,Shanzer, Abraham
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p. 13181 - 13191
(2017/09/26)
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- FLUORESCENT MOLECULAR SENSOR FOR TARGETING CHANGES IN PROTEIN SURFACES, AND METHODS OF USE THEREOF
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This invention is directed to monomolecular sensors, comprising a selective binder, a non-selective binder and a fluorophore, which can track changes that occur on the surface of labeled proteins. This invention is further directed to the use of such sensors for identifying binding partners of specific proteins. This invention is further directed to His-tag binding compounds and uses thereof in the preparation of genetically targeted detectable molecules and sensors which can specifically bind tag-labeled proteins.
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Paragraph 00284
(2015/11/24)
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- CARBOHYDRATE CONJUGATED RNA AGENTS AND PROCESS FOR THEIR PREPARATION
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This disclosure relates to an improved process for the preparation of carbohydrate conjugates. The disclosure also relates to carbohydrate conjugated iRNA agents comprising these carbohydrate conjugates, which have improved purity and are advantageous for the in vivo delivery of the iRNA agents.
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Page/Page column 69; 70
(2014/03/21)
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- Bis Tridentate W3O2 Clusters for X-Ray imaging
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The present invention describes a new class of highly stable W3O2 Clusters, a method for their preparation, their use as X-ray contrast agents and the intermediates tri- or tetracarboxylic acids as desired tridentate ligand resources.
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- Esterified dendritic TAM radicals with very high stability and enhanced oxygen sensitivity
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In this work, we have developed a new class of dendritic TAM radicals (TG, TdG, and dTdG) through a convergent method based on the TAM core CT-03 or its deuterated analogue dCT-03 and trifurcated Newkome-type monomer. Among these radicals, dTdG exhibits the best EPR properties with sharpest EPR singlet and highest O2 sensitivity due to deuteration of both the ester linker groups and the TAM core CT-03. Like the previous dendritic TAM radicals, these new compounds also show extremely high stability toward various reactive species owing to the dendritic encapsulation. The highly charged nature of these molecules resulting from nine carboxylate groups prevents concentration- dependent EPR line broadening at physiological pH. Furthermore, we demonstrate that these TAM radicals can be easily derivatized (e.g., PEGylation) at the nine carboxylate groups and the resulting PEGylated analogue dTdG-PEG completely inhibits the albumin binding, thereby enhancing suitability for in vivo applications. These new dendritic TAM radicals show great potential for in vivo EPR oximetric applications and provide insights on approaches to develop improved and targeted EPR oximetric probes for biomedical applications.
- Song, Yuguang,Liu, Yangping,Hemann, Craig,Villamena, Frederick A.,Zweier, Jay L.
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p. 1371 - 1376
(2013/05/08)
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- DRUG TRANSFER BASED ON COENZYME A AND ACYL CARRIER PROTEIN
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The invention relates to coenzyme A (CoA) type compounds carrying one or more drug entities and optionally a label detectable by a fluorescence detector, magnetic resonance imaging (MRI), positron emission tomography (PET) or scintigraphy, and/or a functi
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(2009/05/29)
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- High-affinity multivalent DNA binding by using low-molecular-weight dendrons
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(Chemical Equation Presented) Nine spermines are better than one: Compound C2 exhibits high-affinity, salt-independent DNA binding as a consequence of the spermine array on its surface. Comparison with smaller dendrons and model compounds indicates a clea
- Kostiainen, Mauri A.,Hardy, John G.,Smith, David K.
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p. 2556 - 2559
(2007/10/03)
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- Self-association of protected Newkome-type second-generation dendrimers at nanomolar level concentrations in aqueous solution
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Protected Newkome-type second-generation dendrimers (based on Lin's amine) were synthesized with a pyrene moiety attached to the core. The photophysical property in aqueous solution of the protected dendrimers shows self-association behavior in water. Pyr
- Mohanty, Subhendu K.,Thirunavukarasu, Shyamala,Baskaran, Sundarababu,Mishra, Ashok E.
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p. 5364 - 5369
(2007/10/03)
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- Macrocyclization on the Fullerene Core: Direct Regio- and Diastereoselective Multi-Functionalization of |60|Fullerene, and Synthesis of Fullerene-dendrimer Derivatives
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The macrocyclization between buckminsterfullerene, C60, and bis-malonate derivatives in a double Bingel reaction provides a versatile and simple method for the preparation of covalent bis-adducts of C60 with high regioand diastereoselectivity. A combination of spectral analysis, stereochemical considerations, and X-ray crystallography (Fig. 2) revealed that out of the possible in-in, in-out, and out-out stereoisomers. the reaction of bis-malonates linked by o-, m-, or p-xylylene tethers afforded only the ouy-out ones (Scheme 1). In contrast, the use of larger tethers derived from 1,10-phenanthroline also provided a first example, (±)-19 (Scheme 2), of an in-out product. Starting from optically pure bis-malonate derivatives, the new bis-functionalization method permitted the diastereoselective preparation of optically active fullerene derivatives (Schemes 4 and 5) and, ultimately, the enantioselective preparation (enantiomeric excess ee > 97%) of optically active cis-3 bis-adducts whose chirality results exclusively from the addition pattern (Fig. 6). The macrocyclic fixation of a bis-malonate with an optically active, 9,9′-spirobi[9H-fluorene]-derived tether to C60 under generation of 24 and ent-24 with an achiral addition pattern (Scheme 4) was found to induce dramatic changes in the chiroptical properties of the tether chromophore such as strong enhancement and reversal of sign of the Cotton effects in the circular dichroism (CD) spectra (Figs. 4 and 5). By the same method, the functionalized bis-adducts 50 and 51 (Schemes 10 and 11) were prepared as initiator cores for the synthesis of the fullerene dendrimers 62, 63, and 66 (Schemes 12 and 13) by convergent growth. Finally, the new methodology was extended to the regio- and diastereoselective construction of higher cyclopropanated adducts. Starting from mono-adduct 71, a clipping reaction provided exclusively the all-cis-2 tris-adduct ( ±)-72 (Scheme 14), whereas the similar reaction of bis-adduct 76 afforded the all-cis-2 tetrakis-adduct 77 (Scheme 15). Electrochemical investigations by steady-state voltammetry (Table2) in CH2Cl2 (+ 0.1M Bu4NPF6) showed that all macrocyclic bis(mcthano)fullerenes underwent multiple reduction steps, and that regioisomerism was not much influencing the redox potentials. All cis-2 bis-adducts gave an instable dianion which decomposed during the electrochemical reduction. In CH2Cl2, the redox potential of the fullerene core in dendrimers 62, 63, and 66 is not affected by differences in size and density of the surrounding poly(ether-amide) dendrons. The all-cis-2 tris- and tetntkis(methano)fullerenes (±)-72 and 77, respectively, are reduced at more negative potential than previously reported all-e tris- and tetrakis-adducts with methano bridges that are also located along an equatorial belt. This indicates a larger perturbation of the original fullerene π-chromophore and a larger raise in LUMO energy in the former derivatives.
- Nierengarten, Jean-Francois,Habicher, Tilo,Kessinger, Roland,Cardullo, Francesca,Diederich, Francois,Graemlich, Volker,Gisselbrecht, Jean-Paul,Boudon, Corinne,Gross, Maurice
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p. 2238 - 2276
(2007/10/03)
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- Polyalkylation of primary polyols by 1,4-addition to tert-butyl acrylate and acrylonitrile
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The very hydrophilic primary polyols pentaerythritol (PE), 1,1,1-tris(hydroxymethyl)ethane and tris(hydroxymethyl)aminomethane (TRIS), can be polyetherified in satisfactory yield by 1,4-addition to tert-butyl acrylate using phase-transfer catalysis. Polycyanoethylation of these polyols can also be accomplished with acrylonitrile. Preliminary results of chelation between some polyether-acids with samarium(III) are presented.
- Dupraz, Agnes,Guy, Philippe,Dupuy, Claude
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p. 1237 - 1240
(2007/10/03)
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