- Synthetic Rhamnose Glycopolymer Cell-Surface Receptor for Endogenous Antibody Recruitment
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Synthetic materials capable of engineering the immune system are of great relevance in the fight against cancer to replace or complement the current monoclonal antibody and cell therapy-based immunotherapeutics. Here, we report on antibody recruiting glyc
- De Coen, Ruben,Nuhn, Lutz,Perera, Chamani,Arista-Romero, Maria,Risseeuw, Martijn D. P.,Freyn, Alec,Nachbagauer, Raffael,Albertazzi, Lorenzo,Van Calenbergh, Serge,Spiegel, David A.,Peterson, Blake R.,De Geest, Bruno G.
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Read Online
- Synthesis of a Tethered myo -Inositol (1,3,4,5,6)Pentakisphosphate (IP5) Derivative as a Probe for Biological Studies
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There is sufficient evidence to suggest that myo-inositol pentakisphosphate is a vital intermediate species in higher inositol phosphate metabolism, however, its biological roles and physiological function in cells remain uncertain. A tethered myo-inosito
- Gregory, Mark,Catimel, Bruno,Yin, Meng-Xin,Condron, Melanie,Burgess, Antony W.,Holmes, Andrew B.
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Read Online
- Oligosaccharide-camptothecin conjugates as potential antineoplastic drugs: Design, synthesis and biological evaluation
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Thirty novel 20 (S)–O-linked camptothecin (CPT) glycoconjugates were synthesized. They showed more potent in vitro cytotoxicities over irinotecan, but very weak direct topoisomerase I (Topo I) inhibition was observed at 100.0 μM. Oligosaccharide types, length of a PEG linker and acetyl groups exerted obvious effects on cytotoxicity, selectivity, water solubility and stability of the newly synthesized CPT glycoconjugates. Construct 40, with a bleomycin (BLM) disaccharide linked to diethylene glycol in the introduced ester moiety, demonstrated a superior antitumor activity and a distinct selectivity compared to CPT. No toxicity was detectable in animal acute toxicity intravenously (160 mg/kg). Collectively, attachment of oligosaccharides with tumor targeting to 20 (S)–OH of CPT could offer a solution to the daunting problems posed by current Topo I poisons.
- Li, Maolin,Ye, Wenchong,Fu, Kaishuo,zhou, Cui,Shi, Yonghui,Huang, Weiping,Chen, Wenming,Hu, Jiliang,Jiang, Zhilin,Zhou, Wen
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- COMPOUNDS AND THERAPEUTIC USES THEREOF
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The invention relates to novel compounds with the ability to link an immune response to a defined therapeutic target, to the use of said compounds in treating cancer and infectious diseases, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.
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Page/Page column 67-68
(2020/05/19)
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- A MedChem toolbox for cereblon-directed PROTACs
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A modular chemistry toolbox was developed for cereblon-directed PROTACs. A variety of linkers was attached to a CRBN ligand via the 4-amino position of pomalidomide. We used linkers of different constitution to modulate physicochemical properties. We equipped one terminus of the linker with a set of functional groups, e.g. protected amines, protected carboxylic acids, alkynes, chloroalkanes, and protected alcohols, all of which are considered to be attractive for PROTAC design. We also highlight different opportunities for the expansion of the medicinal chemists' PROTAC toolbox towards heterobifunctional molecules, e.g. with biotin, fluorescent, hydrophobic and peptide tags.
- Steinebach, Christian,Sosi?, Izidor,Lindner, Stefanie,Bricelj, Ale?a,Kohl, Franziska,Ng, Yuen Lam Dora,Monschke, Marius,Wagner, Karl G.,Kr?nke, Jan,Gütschow, Michael
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supporting information
p. 1037 - 1041
(2019/06/27)
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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 2956; 2957
(2019/07/10)
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- PROTAC-mediated crosstalk between E3 ligases
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Small-molecule heterobifunctional degraders can effectively control protein levels and are useful research tools. We assembled proteolysis targeting chimeras (PROTACs) from a cereblon (CRBN) and a von-Hippel-Lindau (VHL) ligase ligand and demonstrated a PROTAC-induced heterodimerization of the two E3 ligases leading to unidirectional and efficient degradation of CRBN.
- Steinebach, Christian,Kehm, Hannes,Lindner, Stefanie,Vu, Lan Phuong,K?pff, Simon,López Mármol, álvaro,Weiler, Corinna,Wagner, Karl G.,Reichenzeller, Michaela,Kr?nke, Jan,Gütschow, Michael
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supporting information
p. 1821 - 1824
(2019/02/12)
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- Tenofovir derivative and preparation method and application thereof
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The invention discloses a tenofovir derivative and a preparation method and application thereof and belongs to the technical field of antiviral drugs. The tenofovir derivative has antiviral effect, can be enriched in the liver and slowly release active co
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Paragraph 0047; 0048-0049
(2019/11/12)
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- Camptothecin sugar derivative and preparation method and application thereof
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The invention relates to a camptothecin sugar derivative and a preparation method and application thereof, and belongs to the field of biological medicines. The structural formula of the camptothecinsugar derivative is shown in formula (I) in specification. The camptothecin sugar derivative can obviously improve the stability and water solubility of camptothecin and 10-hydroxycamptothecin, and has different sensitivities to different tumor cells. Especially when the chain link n equals to 1, the camptothecin sugar derivative of the invention can significantly increase the selectivity to tumorcells.
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Paragraph 0054-0056; 0058
(2019/11/13)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF BACTERIAL INFECTIONS
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Compositions and methods for the treatment of bacterial infections include compounds containing dimers of cyclic heptapeptides conjugated to one or more monosaccharide or oligosaccharide moieties. In particular, compounds can be used in the treatment of bacterial infections caused by Gram-negative bacteria.
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Page/Page column 177
(2018/02/28)
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- COMPOUNDS USEFUL FOR TREATING GASTROINTESTINAL TRACT DISORDERS
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The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist- induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.
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Paragraph 0424
(2018/07/31)
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- Conjugates between minor groove binders and Zn(II)-tach complexes: Synthesis, characterization, and interaction with plasmid DNA
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A new family of conjugates between a Zn(II)-tach complex and (indole)2 or benzofuran-indole amide minor groove binders connected through alkyl or oxyethyl linkers of different lengths has been prepared. The conjugates bind strongly to DNA. However, the complexation to DNA to promote the Zn(II) catalyzed hydrolytic cleavage of the DNA results instead in its inhibition. This inhibition effect has been confirmed also using Cu(II). Modeling studies suggest that in the most stable complex conformation, the minor groove binder and the linker lie in the minor groove hampering the interaction between the metal complex and the phosphate backbone of DNA. Therefore, the linear arrangement of minor groove binder-linker-metal complex appears to be effective to ensure tight binding but unproductive from a hydrolytic point of view.
- Sissi, Claudia,Dovigo, Luca,Greco, Maria Laura,Ciancetta, Antonella,Moro, Stefano,Trzciński, Jakub W.,Mancin, Fabrizio,Rossi, Paola,Spalluto, Giampiero,Tecilla, Paolo
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p. 3014 - 3024
(2017/04/28)
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- Design, characterization and cellular uptake studies of fluorescence-labeled prototypic cathepsin inhibitors
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Besides their extracellular activity crucial for several pathophysiological conditions, human cysteine cathepsins, in particular cathepsins K and S, represent important intracellular targets for drug development. In the present study, a prototypic dipeptide nitrile inhibitor structure was equipped with a coumarin moiety to function as a fluorescent reporter group. In a second inhibitor, a PEG linker was introduced between the dipeptide nitrile and the fluorophore. These tool compounds 6 and 7 were characterized by kinetic investigations as covalent reversible inhibitors of human cathepsins L, S, K and B. Probe 6 showed a pronounced inhibitory activity against cathepsins K and S, which was corroborated by modeling of inhibition modes. Probe 7 was highly potent (Ki = 93 nM) and selective for cathepsin S. To examine the ability of both probes to enter living cells, human embryonic kidney 293 cells were targeted. At a concentration of 10 μM, cellular uptake of probe 6 was demonstrated by fluorescence measurement after an incubation time of 30 min and 3 h, respectively. The probe's concentration in cell lysates was ascertained on the basis of the emission at 492 nm upon excitation at 450 nm, and the results were expressed as concentrations of probe 6 relative to the protein concentration originating from the lysate. After incubation of 10 μM of probe 6 for 3 h, the cellular uptake was confirmed by fluorescence microscopy. HPLC was used to assess the probes' lipophilicity, and the obtained log:D7.4 value of 2.65 for probe 6 was in agreement with the demonstrated cellular uptake.
- Kohl, Franziska,Schmitz, Janina,Furtmann, Norbert,Schulz-Fincke, Anna-Christina,Mertens, Matthias D.,Küppers, Jim,Benkhoff, Marcel,Tobiasch, Edda,Bartz, Ulrike,Bajorath, Jürgen,Stirnberg, Marit,Gütschow, Michael
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p. 10310 - 10323
(2015/10/28)
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- Separation material comprising phosphoryl choline derivatives
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The present invention provides phosphoryl choline derivatives of general formula (I), which are suitable to be immobilized on a solid support to provide a separation material, which bind with both high affinity and high specificity to a protein, more specifically to C-reactive protein and anti-phosphoryl choline antibodies. Said separation materials are particularly useful in the extracorporeal removal of C-reactive protein and anti-phosphoryl choline antibodies from a biological fluid of a patient for prophylaxis and/or treatment of immune dysfunctions and cardiovascular diseases. Also claimed is a device containing a column that comprises separation material made from formula (I) wherein L is a linker as defined in the claims; X is selected from: -SH, -NHR3, -C=CH, -CH=CH2, -N3, -CHO. Also claimed is a separation material of general formula (II): wherein A is a solid support; Y is a group obtainable from the reactive group X.
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Paragraph 0082; 0083
(2016/01/11)
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- Carbohydrate-based drug delivery polymers and conjugates thereof
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Provided herein are water-soluble carbohydrate polymers which are monoderivatized at their reducing terminus, such that the carbohydrate polymers can be selectively conjugated at a single location. Also provided are methods of preparation and conjugation of the monoderivatized carbohydrate polymers.
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Page/Page column 125
(2015/12/08)
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- SUGAR-LINKER-DRUG CONJUGATES
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The present disclosure relates to sugar-linker-drug conjugates, of the formula [A-B-]n-L-D, wherein A is a saccharide; B is a spacer, n is an integer selected from 1 to 3; L is a linker group and D is a drug having a chemically reactive functional group selected from the group consisting of a primary or secondary amine, hydroxyl, sulfhydryl, carboxyl, aldehyde and ketone. Pharmaceutical compositions comprising the conjugates and methods of using thern are also provided.
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Paragraph 0254
(2014/09/29)
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- SACCHARIDE CONJUGATES
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This invention relates to compounds comprising a saccharide conjugated to an imaging agent or a reporter group, compositions comprising them and methods of using them. Specifically BLM-disaccharide and BLM-monosaccharide conjugates containing different linker groups and an imaging agent or a reporter group are provided for the targeting and imaging of tumors.
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Paragraph 0237; 0247
(2014/10/04)
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- Selective tumor cell targeting by the disaccharide moiety of bleomycin
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In a recent study, the well-documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-
- Yu, Zhiqiang,Schmaltz, Ryan M.,Bozeman, Trevor C.,Paul, Rakesh,Rishel, Michael J.,Tsosie, Krystal S.,Hecht, Sidney M.
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supporting information
p. 2883 - 2886
(2013/04/23)
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- MRI CONTRAST AGENTS
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The present invention relates to MRI based imaging. In particular, the present invention provides MRI contrast agents targeted to a HaloTag protein with tunable relaxation properties thereby providing optimal relaxivity for low field strength imaging and the other optimal relaxivity for high field strength imaging. Moreover, the MRI contrast agents are used to detect gene expression (of a gene of interest) in real time in vivo, to detect changes in gene expression (of a gene of interest) over time in, for example, an individual organism, to detect gene expression changes (of a gene of interest) in response to therapeutics, in cell labeling for MR imaging, in clinical diagnostics, and in theranostics.
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Paragraph 0091; 0092; 0093; 0094
(2013/11/19)
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- CRYSTALLINE CDM-NAG AND METHODS FOR PRODUCING SAME
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The present invention provides a crystalline composition, which comprises CDM-NAG. The present invention also provides a process of producing said crystalline composition, and an improved method of preparing NAG and CDM-NAG.
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Page/Page column 9
(2011/05/11)
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- CARBOHYDRATE-MEDIATED TUMOR TARGETING
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Tumors can be selectively targeted via compounds provided herein according to the formula, or a pharmaceutically acceptable salt thereof, wherein RA and RB are as defined herein. Tumors can be imaged or targeted for therapeutic treat
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Page/Page column 60
(2011/02/24)
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- Reporter protein-targeted probes for magnetic resonance imaging
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Contrast agents for magnetic resonance imaging are frequently employed as experimental and clinical probes. Drawbacks include low signal sensitivity, fast clearance, and nonspecificity that limit efficacy in experimental imaging. In order to create a bioresponsive MR contrast agent, a series of four Gd(III) complexes targeted to the HaloTag reporter were designed and synthesized. HaloTag is unique among reporter proteins for its specificity, versatility, and the covalent interaction between substrate and protein. In similar systems, these properties produce prolonged in vivo lifetimes and extended imaging opportunities for contrast agents, longer rotational correlation times, and increases in relaxivity (r1) upon binding to the HaloTag protein. In this work we report a new MR contrast probe, 2CHTGd, which forms a covalent bond with its target protein and results in a dramatic increase in sensitivity. A 6-fold increase in r1, from 3.8 to 22 mM-1s-1, is observed upon 2CHTGd binding to the target protein. This probe was designed for use with the HaloTag protein system which allows for a variety of substrates (specific for MRI, florescence, or protein purification applications) to be used with the same reporter.
- Strauch, Renee C.,Mastarone, Daniel J.,Sukerkar, Preeti A.,Song, Ying,Ipsaro, Jonathan J.,Meade, Thomas J.
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supporting information; experimental part
p. 16346 - 16349
(2011/12/14)
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- Kinase-mediated trapping of bi-functional conjugates of paclitaxel or vinblastine with thymidine in cancer cells
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In the present work, we explore the possibility of introducing selectivity to existing chemotherapeutics via the design of non-pro-drug, bi-functional molecules comprising a microtubule-binding agent and a substrate for a disease-associated kinase. The design, synthesis, and in vitro biological evaluation of paclitaxel-thymidine and vinblastine-thymidine bi-functional conjugates are reported here. This work provides the first account of 'kinase-mediated trapping' of cancer therapeutics.
- Aspland, Simon E.,Ballatore, Carlo,Castillo, Rosario,Desharnais, Joel,Eustaquio, Trisha,Goelet, Philip,Guo, Zijian,Li, Qing,Nelson, David,Sun, Chengzao,Castellino, Angelo J.,Newman, Michael J.
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p. 5194 - 5198
(2008/02/02)
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- TRICYCLIC COMPOUNDS
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A compound represented by the formula (I) [A represents a 5- to 7-membered hydrocarbon ring group; L represents -NR3-CO-, -CO-NR3- and the like (R3 represents a hydrogen atom, a lower alkyl group, a lower acyl group and the like); M represents an alkylene linking group (a carbon atom constituting the carbon chain may be replaced with a nitrogen atom, an oxygen atom and the like); X represents -S-, -O-, -NR4-, -NR5-CO- and the like (R4 and R5 represent a hydrogen atom, a lower alkyl group and the like) or a single bond; Y represents an alkyl group, an aryl group, an amino group, an aromatic heterocyclic group and the like; R1 represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower acyl group; and R21, R22 and R23 represent a hydrogen atom, a hydroxyl group, a lower alkyl group and the like] or a salt thereof. The compound is useful as an active ingredient of medicaments for diseases in which neuropeptide Y is involved, ingestion control for hyperphagia and the like.
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- Cyanoguanidine compounds
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A cyanoguanidine compound of the following formula: is disclosed. A cyanoguanidine compound of the present invention possess a high specificity for tumor cells. Also disclosed are methods for preparing a cyanoguanidine compound.
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- Design and synthesis of a bifunctional label for selection of β-lactamase displayed on filamentous bacteriophage by catalytic activity
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A bifunctional activity label 1c has been constructed for the selection of active β-lactamases displayed on filamentous bacteriophage. It features an original 6-sulfonylamido-penam sulfone moiety, as β-lactamase suicide-inhibitor, and a biotinyl residue, for separation by affinity chromatography, connected through a linker including a cleavable disulfide bond. The inhibitor 28 resulted from coupling of methoxymethyl 6-aminopenicillinate 8 with N-protected (aminoethoxy)ethoxyethanesulfonyl chloride 23, followed by oxidation into the corresponding sulfone 25, and usual deprotections. The biotinyl ester 32 reacted with 3-(2-aminoethyldithio)propanoic acid 31 as linker, to give 33 which was further activated as pentafluorophenol ester 34b. Final coupling of the building blocks 28 and 34b gave the target label 1c.
- Marchand-Brynaert, Jacqueline,Bouchet, Michele,Touillaux, Roland,Beauve, Cecile,Fastrez, Jacques
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p. 5591 - 5606
(2007/10/03)
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