- Harnessing the Maltodextrin Transport Mechanism for Targeted Bacterial Imaging: Structural Requirements for Improved in vivo Stability in Tracer Design
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Diagnosis and localization of bacterial infections remains a significant clinical challenge. Harnessing bacteria-specific metabolic pathways, such as the maltodextrin transport mechanism, may allow specific localization and imaging of small or hidden colo
- Axer, Alexander,Hermann, Sven,Kehr, Gerald,Clases, David,Karst, Uwe,Fischer-Riepe, Lena,Roth, Johannes,Fobker, Manfred,Sch?fers, Michael,Gilmour, Ryan,Faust, Andreas
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Read Online
- Synergistic effect of zanamivir-porphyrin conjugates on inhibition of neuraminidase and inactivation of influenza virus
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New anti-influenza agents of tetravalent zanamivir on a porphyrin scaffold were synthesized. These compounds are 10 to 100 times more potent in inhibiting influenza replications even though they are somewhat less potent in neuraminidase inhibition than th
- Wen, Wen-Hsien,Lin, Mengi,Su, Ching-Yao,Wang, Shi-Yun,Cheng, Yih-Shyun E.,Fang, Jim-Min,Wong, Chi-Huey
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Read Online
- End-labeled amino terminated monotelechelic glycopolymers generated by ROMP and Cu(I)-catalyzed azide-alkyne cycloaddition
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Functionalizable monotelechelic polymers are useful materials for chemical biology and materials science. We report here the synthesis of a capping agent that can be used to terminate polymers prepared by ring-opening metathesis polymerization of norbornenes bearing an activated ester. The terminating agent is a cis-butene derivative bearing a Teoc (2-trimethylsilylethyl carba-mate) protected primary amine. Post-polymerization modification of the polymer was accomplished by amidation with an azido-amine linker followed by Cu(I)-catalyzed azide-alkyne cycloaddition with propargyl sugars. Subsequent Teoc deprotection and conjugation with pyrenyl isothiocyanates afforded well-defined end-labeled glycopolymers.
- Okoth, Ronald,Basu, Amit
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Read Online
- Catalytic Synthesis of PEGylated EGCG Conjugates that Disaggregate Alzheimer's Tau
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The naturally occurring flavonoid ( )-epigallocatechin gallate (EGCG) is a potent disaggregant of tau fibrils. Guided by the recent cryo-electron microscopy (cryoEM) structure of EGCG bound to fibrils of tau derived from an Alzheimer s brain donor, methods to site-specifically modify the EGCG D-ring with aminoPEGylated linkers are reported. The resultant molecules inhibit tau fibril seeding by Alzheimer s brain extracts. Formulations of aminoPEGylated EGCG conjugated to the (quasi)-brain-penetrant nanoparticle Ferumoxytol inhibit seeding by AD-tau with linker length affecting activity. The protecting groupfree catalytic cycloaddition of amino azides to mono-propargylated EGCG described here provides a blueprint for access to stable nanoparticulate forms of EGCG potentially useful as therapeutics to eliminate Alzheimer s-related tau tangles.
- El Khoury, Anton,Seidler, Paul M.,Eisenberg, David S.,Harran, Patrick G.
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p. 4263 - 4271
(2021/06/18)
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- DINUCLEATING LIGAND OR DINUCLEAR METAL COMPLEX
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To provide a metal complex that has high cancer cell toxicity and has DNA target and cyclen.SOLUTION: The present disclosure provides a dinuclear metal complex represented by the following formula (IV).SELECTED DRAWING: None
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Paragraph 0079-0080
(2021/03/19)
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- A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H3Receptor
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The histamine H3 receptor (H3R) is considered an attractive drug target for various neurological diseases. We here report the synthesis of UR-NR266, a novel fluorescent H3R ligand. Broad pharmacological characterization revealed UR-NR266 as a sub-nanomolar compound at the H3R with an exceptional selectivity profile within the histamine receptor family. The presented neutral antagonist showed fast association to its target and complete dissociation in kinetic binding studies. Detailed characterization of standard H3R ligands in NanoBRET competition binding using UR-NR266 highlights its value as a versatile pharmacological tool to analyze future H3R ligands. The low nonspecific binding observed in all experiments could also be verified in TIRF and confocal microscopy. This fluorescent probe allows the highly specific analysis of native H3R in various assays ranging from optical high throughput technologies to biophysical analyses and single-molecule studies in its natural environment. An off-target screening at 14 receptors revealed UR-NR266 as a selective compound.
- Rosier, Niklas,Gr?tz, Lukas,Schihada, Hannes,M?ller, Jan,I?bilir, Ali,Humphrys, Laura J.,Nagl, Martin,Seibel, Ulla,Lohse, Martin J.,Pockes, Steffen
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p. 11695 - 11708
(2021/08/20)
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- The Synthesis and Biological Evaluation of Some C-9 and C-10 Substituted Derivatives of the RNA Polymerase i Transcription Inhibitor CX-5461
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The regio-isomeric alkynyl-substituted derivatives, 2 and 3, of the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 (1) were prepared and the active one (compound 3) subjected to click reactions ([3 + 2]-cycloaddition reactions) with certain alkyl azides bearing biotin or fluorescent tags. Compounds 2 and 3, as well as four [3 + 2]-cycloadducts of the latter, were subjected to biological evaluation in a human acute myeloid leukemia cell line model. Among the six compounds tested only alkyne 3 remained active but this was less potent than parent 1.
- Amarasiri, Madushani,Vo, Yen,Gardiner, Michael G.,Poh, Perlita,Soo, Priscilla,Pavy, Megan,Hein, Nadine,Ferreira, Rita,Hannan, Katherine M.,Hannan, Ross D.,Banwell, Martin G.
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p. 540 - 556
(2021/04/23)
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- RADIOLABELLED TARGETING LIGANDS
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The present invention relates to compounds that are useful as radioimaging agents and radiopharmaceuticals. The compounds may be coordinated with a radionuclide and may be useful in diagnostic imaging and radiotherapy. The invention also relates to method
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Page/Page column 38; 39; 41
(2021/05/15)
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- Tetrahydroisoquinoline derivative as well as preparation method and medical application thereof
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The invention relates to a tetrahydroisoquinoline derivative, a preparation method thereof and medical application of the tetrahydroisoquinoline derivative. Specifically, the invention relates to a tetrahydroisoquinoline derivative as shown in a general formula (I) and a medicinal salt thereof, a preparation method of the tetrahydroisoquinoline derivative and the medicinal salt thereof, and application of the tetrahydroisoquinoline derivative and the medicinal salt thereof as NHE3 inhibitors, particularly as a therapeutic agent for diseases related to body fluid retention or salt overload or gastrointestinal diseases. Wherein the definition of each substituent in the general formula (I) is the same as the definition in the specification.
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Paragraph 0209; 0218; 0221; 0250-0253
(2021/04/21)
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- Exploration of the Reactivity of Multivalent Electrophiles for Affinity Labeling: Sulfonyl Fluoride as a Highly Efficient and Selective Label
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Here we explored the reactivity of a set of multivalent electrophiles cofunctionalized with a carbohydrate ligand on gold nanoparticles to achieve efficient affinity labeling for target protein analysis. Evaluation of the reactivity and selectivity of the electrophiles against three different cognate binding proteins identified arylsulfonyl fluoride as the most efficient protein-reactive group in this study. We demonstrated that multivalent arylsulfonyl fluoride probe 4 at 50 nm concentration achieved selective affinity labeling and enrichment of a model protein PNA in cell lysate, which was more effective than photoaffinity probe 1 with arylazide group. Labeling site analysis by LC–MS/MS revealed that the nanoparticle-immobilized arylsulfonyl fluoride group can target multiple amino acid residues around the ligand binding site of the target proteins. Our study highlights the utility of arylsulfonyl fluoride as a highly effective multivalent affinity label suitable for covalently capturing unknown target proteins.
- Suto, Nanako,Kamoshita, Shione,Hosoya, Shoichi,Sakurai, Kaori
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p. 17080 - 17087
(2021/07/02)
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- Design and Synthesis of Oleanolic Acid Trimers to Enhance Inhibition of Influenza Virus Entry
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Influenza is a major threat to millions of people worldwide. Entry inhibitors are of particular interest for the development of novel therapeutic strategies for influenza. We have previously discovered oleanolic acid (OA) to be a mild influenza hemagglutinin (HA) inhibitor. In this work, inspired by the 3D structure of HA as a homotrimeric receptor, we designed and synthesized 15 OA trimers with different linkers and central region via the copper-catalyzed azide-alkyne cycloaddition reaction. All of the OA trimers were evaluated for their antiviral activities in vitro, and 12c, 12e, 13c, and 13d were observed to exhibit robust potency (IC50 in the submicromolar range) against influenza A/WSN/33 (H1N1) virus that was stronger than that observed with oseltamivir. In addition, these compounds also displayed strong biological activity against A/Hong Kong/4801/2014 and B/Sichuan/531/2018 (BV). The results of hemagglutination inhibition assays and surface plasmon resonance binding assays suggest that these OA trimers may interrupt the interaction between the HA protein of influenza virus and the host cell sialic acid receptor, thus blocking viral entry. These findings highlight the utility of multivalent OA conjugates to enhance the ligand-target interactions in anti-influenza virus drug design and are also helpful for studying antiviral drugs derived from natural products.
- Huang, Boxuan,Li, Weijia,Mu, Yu,Shao, Liang,Su, Yangqing,Sun, Mengsi,Xu, Huan,Yang, Fan,Yu, Fei,Zhang, Jihong,Zhang, Yuan
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p. 1759 - 1765
(2021/11/18)
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- AGENTS AND METHODS FOR TREATING TAUOPATHIES
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Disclosed are agents that include a flavanol (e.g., epigallocatechm-3-gailate) or a flavanol analog, a linker coupled to the flavanol or the flavanol analog, and a earner (e.g., iron oxide nanoparticle) coupled to the linker. The disclosed agents can be u
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Page/Page column 38; 39
(2021/12/08)
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- Radiopharmaceutical compositions
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The present invention relates to 99mTc-maraciclatide radiopharmaceutical compositions, which are stabilised with a radioprotectant. Also described are kits for the preparation of the radiopharmaceutical compositions, as well methods of preparin
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Page/Page column 23-24
(2020/09/13)
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- Clickable iron oxide NPs based on catechol derived ligands: Synthesis and characterization
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Clickable magnetic nanoparticles have attracted great attention as potential nanoplatforms for biomedical applications because of the high functionalization efficiency of their surfaces with biomolecules, which facilitates their bio-compatibilization. However, the design and synthesis of clickable NPs is still challenging because of the complexity of the chemistry on the magnetic NP surface, thus robust methods that improve the ligand synthesis and the transfer of magnetic NPs in physiological media being in high-demand. In this work, we developed a versatile and enhanced synthetic route to fabricate potentially clickable IONPs of interest in nanomedicine. Catechol anchor ligands with different stereo-electronic features were synthetized from a hetero bi-functional PEG spacer backbone. The resulting catechol ligands transferred in good yields and high stability to magnetic NPs by an improved energetic ligand exchange method that combines sonication and high temperature. The azido functionalized IONPs exhibited excellent characteristics as T2 MRI contrast agents with low cytotoxicity, making these clickable magnetic NPs promising precursors for nanomedicines.
- Pozo-Torres, Esther,Caro, Carlos,Avasthi, Ashish,Páez-Mu?oz, Jose María,García-Martín, María Luisa,Fernández, Inmaculada,Pernia Leal, Manuel
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p. 3257 - 3266
(2020/04/09)
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- Bioorthogonal Ligation and Cleavage by Reactions of Chloroquinoxalines with ortho-Dithiophenols
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A bioorthogonal ligation and cleavage method via reactions of chloroquinoxalines (CQ) and ortho-dithiophenols (DT) is presented. Double nucleophilic substitutions of ortho-dithiophenols to chloroquinoxalines provide conjugates containing tetracyclic benzo[5,6][1,4]dithiino[2,3-b]quinoxaline with strong built-in fluorescence together with release of the other functional molecules. Three cleavable linkers were designed and successfully used in release of the molecules containing biotin from the protein conjugates. The CQ-DT bioorthogonal reactions can be applied for the bioorthogonal ligations, bioorthogonal cleavages, and trans-tagging of proteins, and show advantages of readily accessible unnatural orthogonal groups, appealing reaction kinetics (k2≈1.3 m?1 s?1), excellent biocompatibility of orthogonal groups, and high stability of conjugates. This complements previous bioorthogonal reactions and is a new route for protein-fishing applications and in-gel fluorescence analysis.
- Fu, Hua,Li, Hongyun,Li, Youshan,Lou, Zhenbang,Yang, Haijun,Zhao, Yufen
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supporting information
p. 3671 - 3677
(2020/02/04)
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- Targeted and modular architectural polymers employing bioorthogonal chemistry for quantitative therapeutic delivery
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There remain several key challenges to existing therapeutic systems for cancer therapy, such as quantitatively determining the true, tissue-specific drug release profile in vivo, as well as reducing side-effects for an increased standard of care. Hence, it is crucial to engineer new materials that allow for a better understanding of the in vivo pharmacokinetic/pharmacodynamic behaviours of therapeutics. We have expanded on recent "click-to-release" bioorthogonal pro-drug activation of antibody-drug conjugates (ADCs) to develop a modular and controlled theranostic system for quantitatively assessing site-specific drug activation and deposition from a nanocarrier molecule, by employing defined chemistries. The exploitation of quantitative imaging using positron emission tomography (PET) together with pre-targeted bioorthogonal chemistries in our system provided an effective means to assess in real-time the exact amount of active drug administered at precise sites in the animal; our methodology introduces flexibility in both the targeting and therapeutic components that is specific to nanomedicines and offers unique advantages over other technologies. In this approach, the in vivo click reaction facilitates pro-drug activation as well as provides a quantitative means to investigate the dynamic behaviour of the therapeutic agent.
- Bell, Craig A.,Blinco, James P.,Ediriweera, Gayathri R.,Fletcher, Nicholas L.,Fuchs, Adrian V.,Houston, Zachary H.,Howard, Christopher B.,Mahler, Stephen M.,Simpson, Joshua D.,Thurecht, Kristofer J.,Van De Walle, Matthias,Venkatachalam, Taracad K.
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p. 3268 - 3280
(2020/04/08)
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- BIS(2-HALOACETAMIDO)-COMPOUNDS FOR USE AS LINKING AGENTS AND RESULTANT PRODUCTS WHICH COMPRISE ANTIBODIES, HALF-ANTIBODIES AND ANTIBODY FRAGMENTS
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Bis(2-haloacetamido)- compounds for use as linkers to chemically cross-linking multiple thiol groups, and particularly, although not exclusively, the thiol groups of cysteine amino acids in peptide chains are described, along with their use as linking age
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Page/Page column 27; 32-33
(2021/01/23)
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- Enhanced affinity ligands
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The present invention relates to ligands, nanocrystal complexed with the ligands and their use for bio-imaging.
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Page/Page column 45
(2019/04/10)
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- Assessing Interactions between Helical Aromatic Oligoamide Foldamers and Protein Surfaces: A Tethering Approach
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Helically folded aromatic foldamers may constitute suitable candidates for the ab initio design of ligands for protein surfaces. As preliminary steps toward the exploration of this hypothesis, a tethering approach was developed to detect interactions between a protein and a foldamer by confining the former at the surface of the latter. Cysteine mutants of two therapeutically relevant enzymes, CypA and IL4, were produced. Two series of ten foldamers were synthesized bearing different proteinogenic side chains and either a long or a short linker functionalized with an activated disulfide. Disulfide exchange between the mutated cysteines and the activated disulfides yielded 20 foldamer-IL4 and 20 foldamer-CypA adducts. Effectiveness of the reaction was demonstrated by LC-MS, by MS analysis after proteolytic digestion, and by 2D NMR. Circular dichroism then revealed diastereoselective interactions between the proteins and the foldamers confined at their surface which resulted in a preferred handedness of the foldamer helix. Helix sense bias occurred sometimes with both the short and the long linkers and sometimes with only one of them. In a few cases, helix handedness preference is found to be close to quantitative. These cases constitute valid candidates for structural elucidation of the interactions involved.
- Vallade, Ma?lle,Jewginski, Michal,Fischer, Lucile,Buratto, Jérémie,Bathany, Katell,Schmitter, Jean-Marie,Stupfel, Marine,Godde, Frédéric,Mackereth, Cameron D.,Huc, Ivan
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- Ferrocenyl Janus mixed-dendron stars and their stabilization of Au and Ag nanoparticles
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Janus molecular architectures have recently attracted attention due to their structures and properties that differ from those of traditional symmetric structures. Herein, two new small redox-reversible mixed-dendron star-shape molecules containing three ferrocenyl groups have been synthesized by linking two distinct dendrons using an esterification reaction. These organometallic nano structures were characterized by 1H and 13C NMR, MS, IR and UV–vis. spectroscopies and cyclic voltammetry confirming the number of ferrocenyl groups and AFM and DLS showing micellar assemblies. Au and Ag nanoparticles were stabilized in the presence of a mixed-dendron structure having amidoferrocene termini upon reaction of the nanoparticle metal precursor with NaBH4. Compared reactions of the two star-molecules with HAuCl4 showed a slow redox reaction leading to Au nanoparticles only with the star-molecule terminated with triazolyferrocene termini, which is taken into account by the difference of their redox potentials.
- Liu, Yue,Mu, Shengdong,Liu, Xiong,Ling, Qiangjun,Hang, Chaodong,Ruiz, Jaime,Astruc, Didier,Gu, Haibin
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supporting information
p. 4777 - 4789
(2018/07/31)
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- A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
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Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.
- Lahav, Dani?l,Liu, Bing,Van Den Berg, Richard J.B.H.N.,Van Den Nieuwendijk, Adrianus M. C. H.,Wennekes, Tom,Ghisaidoobe, Amar T.,Breen, Imogen,Ferraz, Maria J.,Kuo, Chi-Lin,Wu, Liang,Geurink, Paul P.,Ovaa, Huib,Van Der Marel, Gijsbert A.,Van Der Stelt, Mario,Boot, Rolf G.,Davies, Gideon J.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
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supporting information
p. 14192 - 14197
(2017/10/17)
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- SYNTHESIS OF NOVEL ASYMMETRIC BOW-TIE PAMAM DENDRIMER-BASED CONJUGATES FOR TUMOR-TARGETING DRUG DELIVERY
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The present disclosure relates to a dendrimer-based conjugate of the formula Vm-D-C-D'-(T-F)n, which is useful for tumor targeting drug delivery. The use of asymmetric dendrimers allow for specific targeting as well as synthetic reproducibility.
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Page/Page column 0073
(2015/03/28)
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- Triazol-substituted titanocenes by strain-driven 1,3-dipolar cycloadditions
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An operationally simple, convenient, and mild strategy for the synthesis of triazole-substituted titanocenes via strain-driven 1,3-dipolar cycloadditions between azide-functionalized titanocenes and cyclooctyne has been developed. It features the first synthesis of titanocenes containing azide groups. These compounds constitute 'second-generation' functionalized titanocene building blocks for further synthetic elaboration. Our synthesis is modular and large numbers of the complexes can in principle be prepared in short periods of time. Some of the triazole-substituted titanocenes display high cyctotoxic activity against BJAB cells. Comparison of the most active complexes allows the identification of structural features essential for biological activity.
- Gansaeuer, Andreas,Okkel, Andreas,Schwach, Lukas,Wagner, Laura,Selig, Anja,Prokop, Aram
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p. 1630 - 1637
(2014/08/05)
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- Efficient synthesis of diverse heterobifunctionalized clickable oligo(ethylene glycol) linkers: Potential applications in bioconjugation and targeted drug delivery
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Herein we describe the sequential synthesis of a variety of azide-alkyne click chemistry-compatible heterobifunctional oligo(ethylene glycol) (OEG) linkers for bioconjugation chemistry applications. Synthesis of these bioorthogonal linkers was accomplished through desymmetrization of OEGs by conversion of one of the hydroxyl groups to either an alkyne or azido functionality. The remaining distal hydroxyl group on the OEGs was activated by either a 4-nitrophenyl carbonate or a mesylate (-OMs) group. The -OMs functional group served as a useful precursor to form a variety of heterobifunctionalized OEG linkers containing different highly reactive end groups, e.g., iodo, -NH2, -SH and maleimido, that were orthogonal to the alkyne or azido functional group. Also, the alkyne- and azide-terminated OEGs are useful for generating larger discrete poly(ethylene glycol) (PEG) linkers (e.g., PEG 16 and PEG24) by employing a Cu(i)-catalyzed 1,3-dipolar cycloaddition click reaction. The utility of these clickable heterobifunctional OEGs in bioconjugation chemistry was demonstrated by attachment of the integrin (αvβ3) receptor targeting peptide, cyclo-(Arg-Gly-Asp-d-Phe-Lys) (cRGfKD) and to the fluorescent probe sulfo-rhodamine B. The synthetic methodology presented herein is suitable for the large scale production of several novel heterobifunctionalized OEGs from readily available and inexpensive starting materials.
- Goswami, Lalit N.,Houston, Zachary H.,Sarma, Saurav J.,Jalisatgi, Satish S.,Hawthorne, M. Frederick
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supporting information
p. 1116 - 1126
(2013/03/28)
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- Design and synthesis of protoporphyrin IX/vitamin B12 molecular hybrids via CuAAC reaction
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The design and synthesis of new molecular hybrids composed of protoporphyrin IX (PPIX) and vitamin B12 via copper catalyzed alkyne azide cycloaddition reaction is described. New, clickable aminoazide and aminoalkyne linkers were prepared and subsequently attached to PPIX (via vinyl group) and to vitamin B12 giving desired building blocks. Preliminary results showed that respective water soluble hybrids were formed under CuAAC reaction. Gratifyingly, Cu incorporation into the PPIX core was avoided, which was important for further biological studies. Copyright
- Loska, Rafa?,Janiga, Anita,Gryko, Dorota
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p. 104 - 117
(2013/04/23)
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- A "Clickable" MTX Reagent as a Practical Tool for Profiling Small-Molecule-Intracellular Target Interactions via MASPIT
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We present a scalable synthesis of a versatile MTX reagent with an azide ligation handle that allows rapid γ-selective conjugation to yield MTX fusion compounds (MFCs) appropriate for MASPIT, a three-hybrid system that enables the identification of mammalian cytosolic proteins that interact with a small molecule of interest. We selected three structurally diverse pharmacologically active compounds (tamoxifen, reversine, and FK506) as model baits. After acetylene functionalization of these baits, MFCs were synthesized via a CuAAC reaction, demonstrating the general applicability of the MTX reagent. In analytical mode, MASPIT was able to give concentration-dependent reporter signals for the established target proteins. Furthermore, we demonstrate that the sensitivity obtained with the new MTX reagent was significantly stronger than that of a previously used non-regiomeric conjugate mixture. Finally, the FK506 MFC was explored in a cellular array screen for targets of FK506. Out of a pilot collection of nearly 2000 full-length human ORF preys, FKBP12, the established target of FK506, emerged as the prey protein that gave the highest increase in luciferase activity. This indicates that our newly developed synthetic strategy for the straightforward generation of MFCs is a promising asset to uncover new intracellular targets using MASPIT cellular array screening.
- Risseeuw, Martijn D. P.,DeClercq, Dries J. H.,Lievens, Sam,Hillaert, Ulrik,Sinnaeve, Davy,VandenBroeck, Freya,Martins, José C.,Tavernier, Jan,VanCalenbergh, Serge
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supporting information
p. 521 - 526
(2013/08/25)
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- A modular approach to triazole-containing chemical inducers of dimerisation for yeast three-hybrid screening
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The yeast three-hybrid (Y3H) approach shows considerable promise for the unbiased identification of novel small molecule-protein interactions. In recent years, it has been successfully used to link a number of bioactive molecules to novel protein binding partners. However despite its potential importance as a protein target identification method, the Y3H technique has not yet been widely adopted, in part due to the challenges associated with the synthesis of the complex chemical inducers of dimerisation (CIDs). The development of a modular approach using potentially "off the shelf" synthetic components was achieved and allowed the synthesis of a family of four triazole-containing CIDs, MTX-Cmpd2.2-2.5. These CIDs were then compared using the Y3H approach with three of them giving a strong positive interaction with a known target of compound 2, TgCDPK1. These results showed that the modular nature of our synthetic strategy may help to overcome the challenges currently encountered with CID synthesis and should contribute to the Y3H approach reaching its full potential as an unbiased target identification strategy.
- Tran, Fanny,Odell, Anahi V.,Ward, Gary E.,Westwood, Nicholas J.
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supporting information
p. 11639 - 11657
(2013/10/22)
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- Fast and efficient MCR-based synthesis of clickable rhodamine tags for protein profiling
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Protein profiling probes are important tools for studying the composition of the proteome and as such have contributed greatly to the understanding of various complex biological processes in higher organisms. For this purpose the application of fluorescently labeled activity or affinity probes is highly desirable. Especially for in vivo detection of low abundant target proteins, otherwise difficult to analyse by standard blotting techniques, fluorescently labeled profiling probes are of high value. Here, a one-pot protocol for the synthesis of activated fluorescent labels (i.e. azide, alkynyl or NHS), based on the Ugi-4-component reaction (Ugi-4CR), is presented. As a result of the peptoidic structure formed, the fluorescent properties of the products are pH insensitive. Moreover, the applicability of these probes, as exemplified by the labeling of model protein BSA, will be discussed.
- Brauch, Sebastian,Henze, Michael,Osswald, Bianca,Naumann, Kai,Wessjohann, Ludger A.,Van Berkel, Sander S.,Westermann, Bernhard
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supporting information; experimental part
p. 958 - 965
(2012/04/10)
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- Unmasking photolithography: A versatile way to site-selectively pattern gold substrates
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Surface chemistry: A new method for creating complex patterns on gold substrates is reported. Substrates were functionalized with nitroveratryl- protected carboxylic acid and hydroxy-terminated thiol monomers and patterned with a direct-write photolithography system to produce complex functional group gradients. In addition, two amine molecules were sequentially coupled on the substrate under spatial control (see picture). Copyright
- Hynes, Matthew J.,Maurer, Joshua A.
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supporting information; experimental part
p. 2151 - 2154
(2012/04/05)
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- A convenient route to diversely substituted icosahedral closomer nanoscaffolds
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The design and synthesis of icosahedral polyhedral borane closomer motifs based upon carbonate and carbamate anchoring groups for biomedical applications are described. Dodecacarbamate closomers containing easily accessible groups of interest at their linker termini were synthesized via activation of the B-OH vertices as aryl carbonates and their subsequent reaction with primary amines. Novel dodecacarbonate closomers were successfully synthesized for the first time by reacting [closo-B12(OH)12]2- with an excess of respective aryl chloroformates, utilizing relatively short reaction times, mild conditions and simple purification strategies, all of which had previously presented difficulties in closomer chemistry. This methodology for the 12-fold degenerate synthesis of carbonate and carbamate closomers will greatly facilitate further exploration of closomers as monodisperse nanomolecular delivery platforms.
- Jalisatgi, Satish S.,Kulkarni, Vikas S.,Tang, Betty,Houston, Zachary H.,Lee, Mark W.,Hawthorne, M. Frederick
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supporting information; scheme or table
p. 12382 - 12385
(2011/10/02)
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- ACYLHYDRAZONE-BASED CLEAVABLE LINKERS
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The present invention provides cleavable linker compounds of Formula (I): wherein: X is a cleavable linker comprising an acylhydrazone; and Y and R are each independently selected from the group consisting of covalent coupling groups and members of a specific binding pair. Solid supports having such cleavable linkers coupled thereto, and methods of using the same, are also described.
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Page/Page column 34-35
(2010/04/03)
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- Activity-based proteome profiling of potential cellular targets of orlistat - An FDA-approved drug with anti-tumor activities
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Orlistat, or tetrahydrolipstatin (THL), is an FDA-approved antiobesity drug with potential antitumor activities. Cellular off-targets and potential side effects of Orlistat in cancer therapies, however, have not been extensively explored thus far. In this study, we report the total of synthesis of THL-like protein-reactive probes, in which extremely conservative modifications (i.e., an alkyne handle) were introduced in the parental THL structure to maintain the native biological properties of Orlistat, while providing the necessary functionality for target identification via the bio-orthogonal click chemistry. With these natural productlike, cell-permeable probes, we were able to demonstrate, for the first time, this chemical proteomic approach is suitable for the identification of previously unknown cellular targets of Orlistat. In addition to the expected fatty acid synthase (FAS), we identified a total of eight new targets, some of which were further validated by experiments including Western blotting, recombinant protein expression, and site-directed mutagenesis. Our findings have important implications in the consideration of Orlistat as a potential anticancer drug at its early stages of development for cancer therapy. Our strategy should be broadly useful for off-target identification against quite a number of existing drugs and/or candidates, which are also covalent modifiers of their biological targets.
- Yang, Peng-Yu,Liu, Kai,Ngai, Mun Hong,Lear, Martin J.,Wenk, Markus R.,Yao, Shao Q.
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supporting information; scheme or table
p. 656 - 666
(2010/03/25)
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- An efficient route to VEGF-like peptide porphyrin conjugates via microwave-assisted 'click-chemistry'
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Synthetic cyclopeptides, and particularly those derived from VEGF sequence, present considerable interest for the development of nanodevices devoted to tumour imaging or targeting. In order to provide selective peptide-targeted tetrapyrrolic structures, w
- Bakleh,Sol,Estieu-Gionnet,Granet,Déléris,Krausz
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experimental part
p. 7385 - 7392
(2009/12/09)
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- Optical Imaging Contrast Agents
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The invention provides contrast agents for optical imaging of vulnerable atherosclerotic plaque in patients. The contrast agents may be used in diagnosis of vulnerable atherosclerotic plaque, for follow up of progress in disease development, for follow up of treatment of vulnerable atherosclerotic plaque and for surgical guidance. Further, the invention provides methods for optical imaging of vulnerable atherosclerotic plaque in patients.
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Page/Page column 12
(2008/06/13)
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- METHODS, COMPOSITIONS, AND KITS FOR THE SELECTIVE ACTIVATION OF PROTOXINS THROUGH COMBINATORIAL TARGETING
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The present invention provides methods and compositions for treating various diseases through selective killipg of targeted cells μsing a combinatorial targeting approach. The invention features protoxin fusion proteins containing a cell targeting rηoiety and, a modifiable activation moiety which is activated by an activation moiety not riaturally operably found in, on, or in the vicinity of a target cell. These methods also include the combinatorial use of two or more therapeutic agents, at minimum comprising a protoxin and a protoxin activator, to target and destroy a specific cell population.
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Page/Page column 174
(2008/06/13)
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- Photocleavable initiator nucleotide substrates for an aldolase ribozyme
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(Chemical Equation Presented) We have previously reported the in vitro selection of a ribozyme that catalyzes an aldol reaction between a levulinic amide aldol donor and a benzaldehyde substrate. The selection scheme involved the priming of the RNA librar
- Fusz, Stefan,Srivatsan, Seergazhi G.,Ackermann, Damian,Famulok, Michael
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p. 5069 - 5077
(2008/12/20)
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- OPTICAL IMAGING
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This invention relates to a method for imaging of wet age-related macular degeneration (AMD) using a contrast agent comprising a vector attached to an optical imaging reporter, wherein the vector has affinity for receptors associated with angiogenesis. Th
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Page/Page column 32
(2008/06/13)
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- IMAGING AGENTS WITH IMPROVED PHARMACOKINETIC PROFILES
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The invention relates to compounds suitable for use in an imaging agent said imaging agent showing an improved pharmacokinetic profile.
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Page/Page column 13
(2010/02/15)
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- Design, synthesis, and evaluation of original carriers for targeting vascular endothelial growth factor receptor interactions
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Purpose. Angiogenesis is a key event in tumor growth and metastasis, chronic inflammatory disease, and cardiovascular disease. It is controlled by positive and negative regulators, which include vascular endothelial growth factor (VEGF) as the most active
- Goncalves, Mario,Estieu-Gionnet, Karine,Berthelot, Thomas,Lain, Georges,Bayle, Mireille,Canron, Xavier,Betz, Natacha,Bikfalvi, Andreas,Deleris, Gerard
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p. 1411 - 1421
(2007/10/03)
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- INHIBITOR IMAGING AGENTS
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The present invention discloses that imaging agents which comprise a specific type of matrix metalloproteinase inhibitors (MMPi's) of the sulphonamide hydroxamate class labelled with an imaging moiety, are useful diagnostic imaging agents for in vivo imag
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Page/Page column 46
(2010/02/12)
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- OPTICAL IMAGING OF COLORECTAL CANCER
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The invention provides contrast agents for optical imaging of colorectal cancer (CRC) in patients. The contrast agents may be used in diagnosis of CRC, for follow up of progress in disease development, and for follow up of treatment of CRC. Further, the i
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- OPTICAL IMAGING CONTRAST AGENTS FOR IMAGING LUNG CANCER
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The invention provides contrast agents for optical imaging of lung cancer in patients. The contrast agents may be used in diagnosis of lung cancer, for follow up of progress in disease development, for follow up of treatment of lung cancer and for surgica
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Page/Page column 27-28
(2008/06/13)
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- OPTICAL IMAGING CONTRAST AGENTS FOR IMAGING LUNG CANCER
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The invention provides contrast agents for optical imaging of prostate cancer in patients. The contrast agents may be used in diagnosis of prostate cancer, for follow up of progress in disease development, for follow up of treatment of prostate cancer and
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Page/Page column 29-30
(2008/06/13)
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- OPTICAL IMAGING CONTRAST AGENTS
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The invention provides contrast agents for optical imaging of oesophageal cancer and Barrett's oesophagus in patients. The contrast agents may be used in diagnosis of oesophageal cancer and Barrett's oesophagus, for follow up of progress in disease develo
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Page/Page column 24
(2008/06/13)
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- Method for sequential support-bound synthesis of conjugated oligomeric compounds
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A sequential support-bound synthesis method is disclosed for preparing a conjugated oligomeric compound, preferably a PNA-peptide conjugate or an oligonucleotide-peptide conjugate, using a bridging molecule having at least two N-protecting amino groups. A conjugated oligomeric compound for therapeutic or prophylactic delivery is also disclosed.
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