- Cyanine compound containing tetrazine unit and preparation method and application thereof
-
The invention provides a cyanine compound containing a tetrazine unit, a preparation method of the cyanine compound and application of the cyanine compound to near-infrared fluorescence labeling of tumor cells by utilizing a biological orthogonal reaction
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Paragraph 0022; 0032-0033
(2021/06/09)
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- MASP-2 INHIBITORS AND METHODS OF USE
-
The present disclosure provides, inter alia, compounds with MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.
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Paragraph 0335; 0340
(2021/06/11)
-
- Selective CRAF Inhibition Elicits Transactivation
-
Discovering molecules that regulate closely related protein isoforms is challenging, and in many cases the consequences of isoform-specific pharmacological regulation remains unknown. RAF isoforms are commonly mutated oncogenes that serve as effector kinases in MAP kinase signaling. BRAF/CRAF heterodimers are believed to be the primary RAF signaling species, and many RAF inhibitors lead to a "paradoxical activation"of RAF kinase activity through transactivation of the CRAF protomer; this leads to resistance mechanisms and secondary tumors. It has been hypothesized that CRAF-selective inhibition might bypass paradoxical activation, but no CRAF-selective inhibitor has been reported and the consequences of pharmacologically inhibiting CRAF have remained unknown. Here, we use bio-orthogonal ligand tethering (BOLT) to selectively target inhibitors to CRAF. Our results suggest that selective CRAF inhibition promotes paradoxical activation and exemplify how BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.
- Morgan, Charles W.,Dale, Ian L.,Thomas, Andrew P.,Hunt, James,Chin, Jason W.
-
supporting information
p. 4600 - 4606
(2021/05/04)
-
- Bioorthogonal "labeling after Recognition" Affording an FRET-Based Luminescent Probe for Detecting and Imaging Caspase-3 via Photoluminescence Lifetime Imaging
-
Bis-labeling with a luminescent energy donor/acceptor pair onto biological substrates affords probes which give FRET readouts for the detection of interaction partners. However, the covalently bound luminophores bring about steric hindrance and nonspecific interaction, which probably perturb the biological recognition. Herein, we designed a highly sensitive and specific "labeling after recognition" sensing approach, where luminophore labeling occurred after the biological recognition. Taking the cutting enzyme caspase-3 as an example, we demonstrated the detection of its catalytic activity in solution and apoptotic cells using the tetrapeptide motif Asp-Glu-Val-Asp (DEVD) as the cleavable substrate, and an iridium(III) complex and a rhodamine derivative as the energy donor/acceptor pair. The DEVD tetrapeptide was modified with an azide and a GK-norbornylene groups at the amino and carboxyl terminuses, respectively, which allowed donor/acceptor bis-labeling via two independent catalysis-free bioorthogonal reactions. The phosphorescence lifetime of the iridium(III) complex was quenched upon bis-labeling owing to the intracellular FRET to the rhodamine derivative, and significantly elongated upon the peptide being catalytically cleaved by caspase-3. Interestingly, the sensitivity and efficiency of the lifetime responses were much higher in the "labeling after recognition" sensing approach. Molecular docking analysis showed that the steric hindrance and nonspecific interactions partially inhibited the biological recognition of the DEVD substrate by caspase-3. The imaging of the catalytic activity of caspase-3 in apoptotic cells was demonstrated via photoluminescence lifetime imaging microscopy. Lifetime analysis not only confirmed the occurrence of intracellular bioorthogonal bis-labeling and catalytic cleavage, but also showed the extent to which the two dynamic processes occurred.
- Dai, Peiling,Huang, Wei,Liu, Shujuan,Song, Linna,Wang, Ling,Wang, Yun,Wu, Qi,Zhang, Kenneth Yin,Zhao, Qiang,Zhu, Hengyu
-
supporting information
p. 1057 - 1064
(2020/02/20)
-
- Inverse Electron-Demand Diels-Alder Bioconjugation Reactions Using 7-Oxanorbornenes as Dienophiles
-
Oligonucleotides, peptides, and peptide nucleic acids incorporating 7-oxanorbornene as a dienophile were reacted with tetrazines linked to either a peptide, d-biotin, BODIPY, or N-acetyl-d-galactosamine. The inverse electron-demand Diels-Alder (IEDDA) cycloaddition, which was performed overnight at 37 °C, in all cases furnished the target conjugate in good yields. IEDDA reactions with 7-oxanorbornenes produce a lower number of stereoisomers than that of IEDDA cycloadditions with other dienophiles.
- Agramunt, Jordi,Ginesi, Rebecca,Grandas, Anna,Pedroso, Enrique
-
p. 6593 - 6604
(2020/07/14)
-
- New 18F-labeled dienophiles and 18F-labeling method using IeDDA reaction with tetrazines
-
The present invention relates to a method of labeling of F-18 radioisotopes using an inverse electron demand Diels-Alder (IeDDA) reaction between a tetrazine compound and a dienophile. A ketone compound according to the present invention easily forms an enamine with a secondary amine in an aqueous solution phase to cause significantly rapid conjugation with a tetrazine compound. Particularly, as the amount of water is increased in the aqueous solution, the reaction proceeds well, so that the compound may be suitable for a bioactive compound, such as a peptide or antibody. Unlike conventional reactions producing different stereoisomers, the reaction produces a small amount of only one type of stereoisomer, besides a main product, and the product can be purified through high performance liquid chromatography, etc. Further, as compared to the conventional ^18F-labeled tetrazine or ^18F-labeled TCO synthesis with a low yield, the ^18F-labeled ketone compound represented by the following chemical formula 1 can be obtained with a high ^18F-labeling yield from a precursor thereof.COPYRIGHT KIPO 2021
- -
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Paragraph 0233-0239
(2020/11/14)
-
- INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
-
The present disclosure discloses compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), which are useful for the prevention and/or the treatment of diseases and disorders associated with defects in NAD+ biosynthesis, e.g., metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with ageing. The present application also discloses pharmaceutical compositions comprising said compounds and the use of such compounds as a medicament.
- -
-
Paragraph 00559
(2020/06/10)
-
- 3-amino-fluorene-2,4-dicarbonitriles (AFDCs) as photocatalysts for the decarboxylative arylation of α-amino acids and α-oxy acids with arylnitriles
-
1-(4-(9H-Carbazol-9-yl)phenyl)-3-amino-9H-fluorene-2,4-dicarbonitrile as a new photocatalyst for the decarboxylative cross-coupling reaction of α-amino acids or α-oxy carboxylic acids with arylnitriles is described. This light-driven reaction enables a va
- Chen, Yiyang,Lu, Ping,Wang, Yanguang
-
supporting information
p. 2130 - 2133
(2019/03/26)
-
- COMPOSITIONS FOR BINDING SPHINGOSINE-1-PHOSPHATE RECEPTOR 1 (S1P1), IMAGING OF S1P1, AND METHODS OF USE THEREOF
-
Among the various aspects of the present disclosure is the provision of a compositions for binding sphingosine-1-phosphate receptor 1 (S1P1), imaging of S1P1, and methods of use thereof. Provided are imaging agents for imaging S1P1 and S1P1 associated diseases, disorders, and conditions. Also provided are therapeutic compositions and methods for the treatment of S1P1 associated diseases, disorders, and conditions.
- -
-
Paragraph 0242-0243
(2019/01/15)
-
- Development of 68Ga-labelled ultrasound microbubbles for whole-body PET imaging
-
Microbubble (MB) contrast agents have revolutionalised the way ultrasound (US) imaging can be used clinically and pre-clinically. Contrast-enhanced US offers improvements in soft-tissue contrast, as well as the ability to visualise disease processes at th
- Hernández-Gil, Javier,Braga, Marta,Harriss, Bethany I.,Carroll, Laurence S.,Leow, Chee Hau,Tang, Meng-Xing,Aboagye, Eric O.,Long, Nicholas J.
-
p. 5603 - 5615
(2019/06/08)
-
- Selective Modification of Ribosomally Synthesized and Post-Translationally Modified Peptides (RiPPs) through Diels–Alder Cycloadditions on Dehydroalanine Residues
-
We report the late-stage chemical modification of ribosomally synthesized and post-translationally modified peptides (RIPPs) by Diels–Alder cycloadditions to naturally occurring dehydroalanines. The tail region of the thiopeptide thiostrepton could be modified selectively and efficiently under microwave heating and transition-metal-free conditions. The Diels–Alder adducts were isolated and the different site- and endo/exo isomers were identified by 1D/2D 1H NMR. Via efficient modification of the thiopeptide nosiheptide and the lanthipeptide nisin Z the generality of the method was established. Minimum inhibitory concentration (MIC) assays of the purified thiostrepton Diels–Alder products against thiostrepton-susceptible strains displayed high activities comparable to that of native thiostrepton. These Diels–Alder products were also subjected successfully to inverse-electron-demand Diels–Alder reactions with a variety of functionalized tetrazines, demonstrating the utility of this method for labeling of RiPPs.
- de Vries, Reinder H.,Viel, Jakob H.,Oudshoorn, Ruben,Kuipers, Oscar P.,Roelfes, Gerard
-
supporting information
p. 12698 - 12702
(2019/09/12)
-
- Syntheses and in vitro evaluation of new S1PR1 compounds and initial evaluation of a lead F-18 radiotracer in rodents
-
Thirteen new sphingosine-1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized by replacing azetidine-3-carboxylic acid moiety of compound 4 with new polar groups. The in vitro binding potency of these new analogs toward S1PR1 was determined. Out of 13 new compounds, four compounds 9a, 10c, 12b, and 16b displayed high S1PR1 binding potency with IC50 values of 13.2 ± 3.2, 14.7 ± 1.7, 9.7 ± 1.6, and 6.3 ± 1.3 nM, respectively; further binding studies of these four ligands toward S1PR2-5 suggested they are highly selective for S1PR1 over other S1PRs. The radiosynthesis of the lead radiotracer [18F]12b was achieved with good radiochemical yield (~14.1%), high radiochemical purity (>98%), and good specific activity (~54.1 GBq/μmol, decay corrected to the end of synthesis, EOS). Ex vivo autoradiography and initial biodistribution studies in rodents were performed, suggesting that [18F]12b was able to penetrate the blood-brain barrier (BBB) with high brain uptake (0.71% ID/g at 60 min post-injection) and no defluorination was observed. In vitro autoradiography study in brain slices of lipopolysaccharides (LPS)-induced neuroinflammation mice indicated that SEW2871, a specific S1PR1 ligand was able to reduce the uptake of [18F]12b, suggesting [18F]12b has S1PR1 specific binding. These initial results suggested that [18F]12b has potential to be an F-18 labeled radiotracer for imaging S1PR1 in the brain of the animal in vivo.
- Luo, Zonghua,Rosenberg, Adam J.,Liu, Hui,Han, Junbin,Tu, Zhude
-
p. 796 - 808
(2018/04/05)
-
- Fast and pH-Independent Elimination of trans-Cyclooctene by Using Aminoethyl-Functionalized Tetrazines
-
The inverse-electron-demand Diels–Alder/pyridazine elimination tandem reaction, in which the allylic substituent on trans-cyclooctene is eliminated following reaction with tetrazines, is gaining interest as a versatile bioorthogonal process. One potential shortcoming of such currently used reactions is their propensity to proceed faster and more efficiently at lower pH, a feature caused by the nature of the tetrazines used. Here, we present aminoethyl-substituted tetrazines as the first pH-independent reagents showing invariably fast elimination kinetics at all biologically relevant pH values.
- Sarris, Alexi J. C.,Hansen, Thomas,de Geus, Mark A. R.,Maurits, Elmer,Doelman, Ward,Overkleeft, Herman S.,Codée, Jeroen D. C.,Filippov, Dmitri V.,van Kasteren, Sander I.
-
supporting information
p. 18075 - 18081
(2018/11/23)
-
- Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction
-
Protein-templated reactions enable the target-guided formation of protein ligands from reactive fragments, ideally with no background reaction. Herein, we investigate the templated formation of amides. A nucleophilic fragment that binds to the coagulation factor Xa was incubated with the protein and thirteen differentially activated dipeptides. The protein induced a non-catalytic templated reaction for the phenyl and trifluoroethyl esters; the latter was shown to be a completely background-free reaction. Starting from two fragments with millimolar affinity, a 29 nm superadditive inhibitor of factor Xa was obtained. The fragment ligation reaction was detected with high sensitivity by an enzyme activity assay and by mass spectrometry. The reaction progress and autoinhibition of the templated reaction by the formed ligation product were determined, and the structure of the protein–inhibitor complex was elucidated.
- Jaegle, Mike,Steinmetzer, Torsten,Rademann, J?rg
-
supporting information
p. 3718 - 3722
(2017/03/21)
-
- 1,3,4-OXADIAZOLE SULFONAMIDE DERIVATIVE COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITOR, AND THE PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
-
The present invention relates to novel compounds represented by the formula I having histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, the use thereof for the preparation of therapeutic medicaments, pharmaceutical compositions containing the same, a method for treating diseases using the composition, and methods for preparing the novel compounds. (I) The novel compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof according to the present invention have histone deacetylase (HDAC) inhibitory activity and are effective for the prevention or treatment of HDAC6-mediated diseases.
- -
-
Paragraph 1552; 1553; 1554
(2017/02/24)
-
- LABELING OF ANTIBODIES
-
Provided herein are methods for producing site specific PEG modifications to single domain antibodies (e.g., VHHs). Methods for producing site- specific ally conjugated bivalent single domain antibodies (e.g., VHHs) are also provided. Methods for labeling
- -
-
Paragraph 00341
(2017/08/01)
-
- Enzyme-Mediated Modification of Single-Domain Antibodies for Imaging Modalities with Different Characteristics
-
Antibodies are currently the fastest-growing class of therapeutics. Although naked antibodies have proven valuable as pharmaceutical agents, they have some limitations, such as low tissue penetration and a long circulatory half-life. They have been conjugated to toxic payloads, PEGs, or radioisotopes to increase and optimize their therapeutic efficacy. Although nonspecific conjugation is suitable for most in vitro applications, it has become evident that site specifically modified antibodies may have advantages for in vivo applications. Herein we describe a novel approach in which the antibody fragment is tagged with two handles: One for the introduction of a fluorophore or 18F isotope, and the second for further modification of the fragment with a PEG moiety or a second antibody fragment to tune its circulatory half-life or its avidity. Such constructs, which recognize Class II MHC products and CD11b, showed high avidity and specificity. They were used to image cancers and could detect small tumors.
- Rashidian, Mohammad,Wang, Lu,Edens, Jerre G.,Jacobsen, Johanne T.,Hossain, Intekhab,Wang, Qifan,Victora, Gabriel D.,Vasdev, Neil,Ploegh, Hidde,Liang, Steven H.
-
supporting information
p. 528 - 533
(2016/02/27)
-
- 4-ALKYNYL IMIDAZOLE DERIVATIVE AND MEDICINE COMPRISING SAME AS ACTIVE INGREDIENT
-
There are provided 4-alkynylimidazole derivatives represented by the following general formula (I) or phamaceutically acceptable salts thereof; the derivatives have a superior EP4 receptor antagonistic action and are useful as pharmaceuticals for the trea
- -
-
Paragraph 0296
(2016/06/06)
-
- 4-ALKYNYL IMIDAZOLE DERIVATIVE AND MEDICINE COMPRISING SAME AS ACTIVE INGREDIENT
-
There are provided 4-alkynylimidazole derivatives represented by the following general formula (I) or phamaceutically acceptable salts thereof; the derivatives have a superior EP4 receptor antagonistic action and are useful as pharmaceuticals for the trea
- -
-
Paragraph 0463; 0464
(2016/10/10)
-
- Novel Super-Resolution Imaging Compositions and Methods Using Same
-
The invention provides compositions that may be used for imaging intracellular structures. The invention further provides methods of imaging intracellular structures. In certain embodiments, the compositions of the invention include trans-cyclooctene-containing ceramide lipids and tetrazine-containing rhodamine-related dyes.
- -
-
Paragraph 0149-0152
(2016/05/24)
-
- Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor
-
PACE4 plays an important role in the progression of prostate cancer and is an attractive target for the development of novel inhibitor-based tumor therapies. We previously reported the design and synthesis of a novel, potent, and relatively selective PACE4 inhibitor known as a Multi-Leu (ML) peptide. In the present work, we examined the ML peptide through detailed structure-activity relationship studies. A variety of ML-peptide analogues modified at the P8-P5 positions with leucine isomers (Nle, DLeu, and DNle) or substituted at the P1 position with arginine mimetics were tested for their inhibitory activity, specificity, stability, and antiproliferative effect. By incorporating d isomers at the P8 position or a decarboxylated arginine mimetic, we obtained analogues with an improved stability profile and excellent antiproliferative properties. The DLeu or DNle residue also has improved specificity toward PACE4, whereas specificity was reduced for a peptide modified with the arginine mimetic, such as 4-amidinobenzylamide.
- Kwiatkowska, Anna,Couture, Frédéric,Levesque, Christine,Ly, Kévin,Desjardins, Roxane,Beauchemin, Sophie,Prahl, Adam,Lammek, Bernard,Neugebauer, Witold,Dory, Yves L.,Day, Robert
-
-
- A bioorthogonal 68Ga-labelling strategy for rapid in vivo imaging
-
Herein, we describe a fast and robust method for achieving 68Ga-labelling of the EGFR-selective monoclonal antibody (mAb) Cetuximab using the bioorthogonal Inverse-electron-Demand Diels-Alder (IeDDA) reaction. The in vivo imaging of EGFR is demonstrated, as well as the translation of the method within a two-step pretargeting strategy. This journal is the Partner Organisations 2014.
- Evans, Helen L.,Nguyen, Quang-De,Carroll, Laurence S.,Kaliszczak, Maciej,Twyman, Frazer J.,Spivey, Alan C.,Aboagye, Eric O.
-
supporting information
p. 9557 - 9560
(2014/08/18)
-
- Super-resolution imaging of the Golgi in live cells with a bioorthogonal ceramide probe
-
We report a lipid-based strategy to visualize Golgi structure and dynamics at super-resolution in live cells. The method is based on two novel reagents: a trans-cyclooctene-containing ceramide lipid (Cer-TCO) and a highly reactive, tetrazine-tagged near-IR dye (SiR-Tz). These reagents assemble via an extremely rapid "tetrazine-click" reaction into Cer-SiR, a highly photostable "vital dye" that enables prolonged live-cell imaging of the Golgi apparatus by 3D confocal and STED microscopy. Cer-SiR is nontoxic at concentrations as high as 2 μM and does not perturb the mobility of Golgi-resident enzymes or the traffic of cargo from the endoplasmic reticulum through the Golgi and to the plasma membrane.
- Erdmann, Roman S.,Takakura, Hideo,Thompson, Alexander D.,Rivera-Molina, Felix,Allgeyer, Edward S.,Bewersdorf, Joerg,Toomre, Derek,Schepartz, Alanna
-
supporting information
p. 10242 - 10246
(2015/03/31)
-
- Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design
-
β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.
- Mok, N. Yi,Chadwick, James,Kellett, Katherine A. B.,Casas-Arce, Eva,Hooper, Nigel M.,Johnson, A. Peter,Fishwick, Colin W. G.
-
supporting information
p. 1843 - 1852
(2013/05/08)
-
- INHIBITORS OF FURIN AND OTHER PRO-PROTEIN CONVERTASES
-
Disclosed herein are Furin/PC inhibitors for inhibiting Furin and other Propprotein Convertases. Method of making the Furin/PC inhibitors, chemical and biological characterization of the Furin/PC inhibitors, and the use of the Furin/PC inhibitors to treat
- -
-
Paragraph 00095
(2013/09/26)
-
- Pd-catalyzed Suzuki-Miyaura cross-coupling reactions between sulfamates and potassium Boc-protected aminomethyltrifluoroborates
-
Sulfamates were studied as the electrophilic partners in the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction with potassium Boc-protected primary and secondary aminomethyltrifluoroborates. A broad range of substrates was successfully coupled to provide the desired products. Complex molecules containing a new carbon-carbon bond and an aminomethyl moiety could be prepared through this developed method.
- Molander, Gary A.,Shin, Inji
-
supporting information
p. 2534 - 2537
(2013/06/27)
-
- Suzuki-Miyaura cross-coupling reactions of potassium boc-protected aminomethyltrifluoroborate with aryl and hetaryl mesylates
-
Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions were studied with potassium Boc-protected aminomethyltrifluoroborate through C-O activation of various mesylate derivatives to afford the corresponding products in moderate to good yields.
- Molander, Gary A.,Shin, Inji
-
supporting information; experimental part
p. 3138 - 3141
(2012/08/07)
-
- Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction
-
E3 ubiquitin ligases, which bind protein targets, leading to their ubiquitination and subsequent degradation, are attractive drug targets due to their exquisite substrate specificity. However, the development of small-molecule inhibitors has proven extrao
- Buckley, Dennis L.,Van Molle, Inge,Gareiss, Peter C.,Tae, Hyun Seop,Michel, Julien,Noblin, Devin J.,Jorgensen, William L.,Ciulli, Alessio,Crews, Craig M.
-
p. 4465 - 4468
(2012/04/23)
-
- Triple bioorthogonal ligation strategy for simultaneous labeling of multiple enzymatic activities
-
Three at the same time: A ligation strategy combining tetrazine-norbornene cycloaddition, Staudinger-Bertozzi ligation, and copper(I)-catalyzed click reaction was used to label the three catalytic activities of the proteasome simultaneously in a single experiment. The orthogonality of the three ligation reactions enables selective monitoring of multiple targets at the same time in complex biological samples. Copyright
- Willems, Lianne I.,Li, Nan,Florea, Bogdan I.,Ruben, Mark,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.
-
supporting information; experimental part
p. 4431 - 4434
(2012/06/18)
-
- Genetic encoding of bicyclononynes and trans-cyclooctenes for site-specific protein labeling in vitro and in live mammalian cells via rapid fluorogenic diels-alder reactions
-
Rapid, site-specific labeling of proteins with diverse probes remains an outstanding challenge for chemical biologists. Enzyme-mediated labeling approaches may be rapid but use protein or peptide fusions that introduce perturbations into the protein under study and may limit the sites that can be labeled, while many "bioorthogonal" reactions for which a component can be genetically encoded are too slow to effect quantitative site-specific labeling of proteins on a time scale that is useful for studying many biological processes. We report a fluorogenic reaction between bicyclo[6.1.0]non-4-yn-9- ylmethanol (BCN) and tetrazines that is 3-7 orders of magnitude faster than many bioorthogonal reactions. Unlike the reactions of strained alkenes, including trans-cyclooctenes and norbornenes, with tetrazines, the BCN-tetrazine reaction gives a single product of defined stereochemistry. We have discovered aminoacyl-tRNA synthetase/tRNA pairs for the efficient site-specific incorporation of a BCN-containing amino acid, 1, and a trans-cyclooctene- containing amino acid 2 (which also reacts extremely rapidly with tetrazines) into proteins expressed in Escherichia coli and mammalian cells. We demonstrate the rapid fluorogenic labeling of proteins containing 1 and 2 in vitro, in E. coli, and in live mammalian cells. These approaches may be extended to site-specific protein labeling in animals, and we anticipate that they will have a broad impact on labeling and imaging studies.
- Lang, Kathrin,Davis, Lloyd,Wallace, Stephen,Mahesh, Mohan,Cox, Daniel J.,Blackman, Melissa L.,Fox, Joseph M.,Chin, Jason W.
-
supporting information; experimental part
p. 10317 - 10320
(2012/08/08)
-
- Synthesis and Suzuki-Miyaura cross-coupling reactions of potassium Boc-protected aminomethyltrifluoroborate with aryl and hetaryl halides
-
Potassium Boc-protected aminomethyltrifluoroborate, a primary aminomethyl equivalent, was synthesized successfully through a "one-pot" process. With this trifluoroborate, Suzuki-Miyaura cross-coupling reactions were investigated with a variety of both aryl and hetaryl chlorides in good to excellent yields.
- Molander, Gary A.,Shin, Inji
-
p. 3956 - 3959
(2011/10/03)
-
- Synthesis and application of a new fluorous-tagged ammonia equivalent
-
A novel fluorous-tagged ammonia equivalent has been developed. It is based on a nitrogen-oxygen bond, which can be cleaved in a traceless manner by a molybdenum complex or samarium diiodide. The application in the synthesis of ureas, amides, sulfonamides, and carbamates is described. The scope of the fluo-rous N-O linker is exemplified by the synthesis of itopride, a drug used for the treatment of functional dyspepsia. Itopride was synthesized with the aid of fluorous purification methods and the product was isolated in good overall yield, with high purity.
- Nielsen, Simon D.,Smith, Garrick,Begtrup, Mikael,Kristensen, Jesper L.
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supporting information; experimental part
p. 4557 - 4566
(2010/08/20)
-
- TRIAZOLE OXADIAZOLES DERIVATIVES
-
The invention relates to compounds of formula (I), wherein R1, R2, Ra, Rb, X have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis.
- -
-
Page/Page column 112-113
(2009/07/25)
-
- OXADIAZOLE DERIVATIVES WITH ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE PROPERTIES
-
Disclosed are polycyclic compounds of the following formula (I) and their use as anti-inflammatory and immunosuppressive agents.
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-
Page/Page column 12
(2008/06/13)
-
- Ring opening of 2-(benzylamino)-2H-1,4-benzoxazin-3(4H)-ones and 2-bromo-2H-1,4-benzoxazin-3(4H)-ones
-
Substituted 2-(benzylamino)-2H-1,4-benzoxazin-3(4H)-ones are unstable under alkaline and acidic conditions, undergoing opening of the benzoxazinone ring. 2-Bromo-2H-1,4-benzoxazin-3(4H)-ones show similar degradation under alkaline conditions, while replacement of Br at C(2) to give 2-hydroxy-2H-1,4-benzoxazin- 3(4H)-ones was observed only under mild alkaline conditions. Mechanisms of ring opening and degradation to 2-aminophenol derivatives are proposed.
- Ilas, Janez,Kikelj, Danijel
-
experimental part
p. 654 - 664
(2009/02/07)
-
- Base-substituted benzylamine analogs for use as coagulation factor xa inhibitors, the production and use thereof
-
The invention relates to the novel base-substituted benzylamine analogs of general formula (I), wherein A represents P2-P1 with P1=(A) and P2=(B), for use as coagulation factor Xa inhibitors. The invention also relates to the production and use of said analogs in the therapy and prophylaxis of cardiovascular diseases and thromboembolic events.
- -
-
Page/Page column 8
(2008/06/13)
-
- PROCESS FOR PREPARING PROTECTED AMIIDINES
-
A process for preparing a protected amidine group of formula (I): wherein R6 represents, for example, C1-10 alkyl (optionally substituted), aryl, C1-3 alkylaryl or C1-3 alkyloxyaryl; which comprises reacting a n
- -
-
Page/Page column 15-16
(2008/06/13)
-
- Unexpected enhancement of thrombin inhibitor potency with o-aminoalkylbenzylamides in the P1 position
-
Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the α-thrombin-hirugen complex provides an explanation for these unanticipated results.
- Rittle, Kenneth E.,Barrow, James C.,Cutrona, Kellie J.,Glass, Kristen L.,Krueger, Julie A.,Kuo, Lawrence C.,Lewis, S. Dale,Lucas, Bobby J.,McMasters, Daniel R.,Morrissette, Matthew M.,Nantermet, Philippe G.,Newton, Christina L.,Sanders, William M.,Yan, Youwei,Vacca, Joseph P.,Selnick, Harold G.
-
p. 3477 - 3482
(2007/10/03)
-
- 4-Amidinobenzylamine-Based Inhibitors of Urokinase
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A series of 4-amidinobenzylamine-based peptidomimetic inhibitors of urokinase was synthesized. The most potent one, benzylsulfonyl-D-Ser-Ala-4-amidinobenzylamide 16, inhibits uPA with a Ki of 7.7 nM but is less selective than 10 with a Gly as P2 residue. Hydroxyamidine and carbonate prodrugs were prepared, which are rapidly converted into the active inhibitors in rats after subcutaneous application.
- Kuenzel, Sebastian,Schweinitz, andrea,Reissmann, Siegmund,Stuerzebecher, Joerg,Steinmetzer, Torsten
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p. 644 - 648
(2007/10/03)
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the Formula IX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- Large scale preparation of protected 4-aminomethylbenzamidine. Application to the synthesis of the thrombin inhibitor, melagatran
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To allow the preparation of melagatran on a multigram scale, we have investigated several approaches for the synthesis of the key intermediate 4- aminomethylbenzamidine. The only industrially suitable pathway relies on the preparation of an N-hydroxyimino
- Lila, Christine,Gloanec, Philippe,Cadet, Laurence,Herve, Yolande,Fournier, Jean,Leborgne, Fabrice,Verbeuren, Tony J.,De Nanteuil, Guillaume
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p. 4419 - 4429
(2007/10/03)
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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