- Zinc(II)cyclen-peptide conjugates interacting with the weak effector binding state of Ras
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Zinc(II)cyclen-peptide hybrid compounds and bis-zinc(II)cyclen complexes are prepared as potential binders of the guanine nucleotide binding protein Ras, an important molecular switch in cellular signal transduction. The design of the compounds is based on the previous observation that zinc(II)cyclen complexes could serve as lead compounds for inhibitors of Ras-effector interaction and thus be able to interrupt Ras induced signal transduction. Zinc(II)cyclen selectively stabilizes conformational state 1 of active Ras, a conformational state with drastically decreased affinity to effector proteins like Raf-kinase. To achieve higher binding affinities of such Ras-Raf interaction inhibitors, zinc(II)cyclen conjugates with short peptides, derived from the sequence of the Ras-activator SOS, were prepared by solid phase synthesis protocols. Dinuclear bis-zinc(II)cyclen complexes were obtained from alkyne-azide cycloaddition reactions. NMR investigations of the prepared compounds revealed that the peptide conjugates do not lead to an increase in Ras binding affinity of the metal complex-peptide conjugates. The dinuclear zinc complexes lead to an immediate precipitation of the protein prohibiting spectroscopic investigations of their binding.
- Schmidt, Florian,Rosnizeck, Ina C.,Spoerner, Michael,Kalbitzer, Hans Robert,K?nig, Burkhard
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- Living ring-opening metathesis-polymerization synthesis and redox-sensing properties of norbornene polymers and copolymers containing ferrocenyl and tetraethylene glycol groups
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The controlled synthesis of monodisperse, redox-active metallopolymers and their redox properties and functions, including robust electrode derivatization and sensing, remains a challenge. Here a series of polynorbornene homopolymers and block copolymers containing side-chain amidoferrocenyl groups and tetraethylene glycol linkers were prepared via living ring-opening metathesis polymerization initiated by Grubbs' third-generation catalyst (1). Their molecular weights were determined using MALDI-TOF mass spectra, size exclusion chromatography (SEC), end-group analysis, and the empirical Bard-Anson electrochemical equation. All polymerizations followed a living and controlled manner, and the number of amidoferrocenyl units varied from 5 to 332. These homopolymers and block copolymers were successfully used to prepare modified Pt electrodes that showed excellent stability. The modified Pt electrodes show excellent qualitative sensing of ATP2- anions, in particular those prepared with the block copolymers. The quantitative recognition and titration of [n-Bu4N]2[ATP] was carried out using the CH 2Cl2 solution of the homopolymers, showing that two amidoferrocenyl groups of the homopolymers interacted with each ATP2- molecule. This stoichiometry led us to propose the H-bonding modes in the supramolecular polymeric network.
- Gu, Haibin,Rapakousiou, Amalia,Castel, Patricia,Guidolin, Nicolas,Pinaud, Noeel,Ruiz, Jaime,Astruc, Didier
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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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- 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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- Tetraethylene glycol-derived spacer for oligonucleotide synthesis
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3,6,9-Trioxaundecane-1,11-diisocyanate (6) was synthesised from tetraethylene glycol in 5 steps and 48 % overall yield. Spacer 6 was monofunctionalised with the fully protected adenosyl-3'-O-succinate derivative 7 and linked to aminomethyl polystyrene affording a solid support suitable for oligoribonucleotide synthesis (loading: ~20 μmol/g). The HPLC analysis of a crude oligoribonucleotide synthesis and the yield of the full- length product show that this spacer compares well to hexamethylene diamine.
- Gunzenhauser,Biala,Strazewski
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- Synthesis of calix[4]crowns containing soft and hard ion binding sites via click chemistry
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A series of triazole-modified calix[4]crowns, 3, containing hard and soft ion binding sites were synthesized in good yields via click chemistry. The hard and soft ion binding sites may selectively complex alkali metal or transition metal cations. Compound 3a shows good complex selectivity towards Pb 2+ and 3c shows the highest Li+/K+ extraction ratio, suggesting that the triazole groups play an important role in metal ion binding.
- Zhan, Junyan,Tian, Demei,Li, Haibing
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- Synthesis of peptide homo- and heterodimers as potential mimics of platelet-derived growth factor BB
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Pericyte loss is correlated with blood-brain barrier leakage in neurological disorders such as Alzheimer's disease. The platelet-derived growth factor receptor β (PDGFRβ)/platelet-derived growth factor BB (PDGF-BB) signalling pathway is key to the regulation of pericyte survival and proliferation. A series of peptide dimers mimicking the ligand PDGF-BB were prepared in the hope of stimulating PDGFRβ internalisation and activation of this pathway. Copper-catalysed azide-alkyne cycloaddition of peptide monomers with PEGylated linkers of varying length afforded the desired peptide dimers. Evaluation of the peptide dimers in human brain pericyte assays revealed no effect on PDGFRβ internalisation nor cell proliferation at concentrations 10 μM. The peptide dimers also did not act as antagonists at PDGFRβ at concentrations 10 μM.
- Stubbing, Louise A.,Kaur, Harveen,Feng, Sheryl X.,Aalderink, Miranda,Dragunow, Michael,Brimble, Margaret A.
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- Multimeric Near IR-MR Contrast Agent for Multimodal in Vivo Imaging
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Multiple imaging modalities are often required for in vivo imaging applications that require both high probe sensitivity and excellent spatial and temporal resolution. In particular, MR and optical imaging are an attractive combination that can be used to determine both molecular and anatomical information. Herein, we describe the synthesis and in vivo testing of two multimeric NIR-MR contrast agents that contain three Gd(III) chelates and an IR-783 dye moiety. One agent contains a PEG linker and the other a short alkyl linker. These agents label cells with extraordinary efficacy and can be detected in vivo using both imaging modalities. Biodistribution of the PEGylated agent shows observable fluorescence in xenograft MCF7 tumors and renal clearance by MR imaging. (Figure Presented).
- Harrison, Victoria S. R.,Carney, Christiane E.,MacRenaris, Keith W.,Waters, Emily A.,Meade, Thomas J.
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- Polyacrylamide pseudo crown ethers via hydrogen bond-assisted cyclopolymerization
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Polyacrylamide pseudo crown ethers with large in-chain rings (15–24 membered) were synthesized by hydrogen bond-mediated cyclopolymerization of bisacrylamides comprising poly(ethylene oxide) spacers (PEGnDAAm, ethylene oxide units: n = 3–6). The monomers undergo the intramolecular hydrogen bonding of the bisacrylamide units in halogenated solvents to dynamically place the two olefins adjacently. As a result, the bisacrylamides homogeneously allowed controlled radical cyclopolymerization without any macroscopic gelation in 1,2-dichloroethane, even at relatively high concentration of monomers (200 mM), to directly provide precision cyclopolyacrylamides and the related copolymers with high cyclization efficiency (84–98%). Owing to the in-chain ring pendants, a cyclopolyacrylamide had glass transition temperature higher than a corresponding polyacrylamide with linear pendants.
- Kimura, Yoshihiko,Miyabara, Yuichiro,Terashima, Takaya,Sawamoto, Mitsuo
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- Synthesis of orthogonal end functionalized oligoethylene glycols of defined lengths
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The synthesis of oligoethylene glycols of defined lengths possessing different end functionalities is described. The utility of these molecules towards the development of a generic membrane anchor is demonstrated.
- Iyer, Suri S.,Anderson, Aaron S.,Reed, Scott,Swanson, Basil,Schmidt, Jürgen G.
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- 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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- 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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- Cyto-mechanoresponsive polyelectrolyte multilayer films
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Cell adhesion processes take place through mechanotransduction mechanisms where stretching of proteins results in biological responses. In this work, we present the first cyto-mechanoresponsive surface that mimics such behavior by becoming cell-adhesive t
- Davila, Johanna,Chassepot, Armelle,Longo, Johan,Boulmedais, Fouzia,Reisch, Andreas,Frisch, Benoit,Meyer, Florent,Voegel, Jean-Claude,Mesini, Philippe J.,Senger, Bernard,Metz-Boutigue, Marie-Helene,Hemmerle, Joseph,Lavalle, Philippe,Schaaf, Pierre,Jierry, Loic
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- Bivalent HIV-1 fusion inhibitors based on peptidomimetics
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Membrane fusion is a valid target for inhibition of HIV-1 replication. A 34-mer fragment peptide (C34), which is contained in the HIV-1 envelope protein gp41, has significant anti-HIV activity. Previously, a dimeric derivative of C34 linked by a disulfide bridge at its C-terminus was found to have more potent anti-HIV activity than the C34 peptide monomer. To date, several peptidomimetic small inhibitors have been reported, but most have lower potency than peptide derivatives related to C34. In the present study we applied this dimerization concept to these peptidomimetic small inhibitors and designed several bivalent peptidomimetic HIV-1 fusion inhibitors. The importance of the length of linkers crosslinking two peptidomimetic compounds was demonstrated and several potent bivalent inhibitors containing tethered peptidomimetics were produced.
- Kobayakawa, Takuya,Ebihara, Kento,Tsuji, Kohei,Kawada, Takuma,Fujino, Masayuki,Honda, Yuzuna,Ohashi, Nami,Murakami, Tsutomu,Tamamura, Hirokazu
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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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- Strain-Induced Reactivity in the Dynamic Covalent Chemistry of Macrocyclic Imines
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The displacement of molecular structures from their thermodynamically most stable state by imposition of various types of electronic and conformational constraints generates highly strained entities that tend to release the accumulated strain energy by undergoing either structural changes or chemical reactions. The latter case amounts to strain-induced reactivity (SIR) that may enforce specific chemical transformations. A particular case concerns dynamic covalent chemistry which may present SIR, whereby reversible reactions are activated by coupling to a high-energy state. We herewith describe such a dynamic covalent chemical (DCC) system involving the reversible imine formation reaction. It is based on the formation of strained macrocyclic bis-imine metal complexes in which the macrocyclic ligand is in a high energy form enforced by the coordination of the metal cation. Subsequent demetallation generates a highly strained free macrocycle that releases its accumulated strain energy by hydrolysis and reassembly into a resting state. Specifically, the metal-templated condensation of a dialdehyde with a linear diamine leads to a bis-imine [1+1]-macrocyclic complex in which the macrocyclic ligand is in a coordination-enforced strained conformation. Removal of the metal cation by a competing ligand yields a highly reactive [1+1]-macrocycle, which then undergoes hydrolysis to transient non-cyclic aminoaldehyde species, which then recondense to a strain-free [2+2]-macrocyclic resting state. The process can be monitored by 1H NMR spectroscopy. Energy differences between different conformational states have been evaluated by Hartree-Fock (HF) computations. One may note that the stabilisation of high-energy molecular forms by metal ion coordination followed by removal of the latter, offers a general procedure for producing out-of-equilibrium molecular states, the fate of which may then be examined, in particular when coupled to dynamic covalent chemical processes.
- Ratjen, Lars,Vantomme, Ghislaine,Lehn, Jean-Marie
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- Synthesis and metal-binding properties of novel "fullerenocrowns"
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"Fullerenocrowns" in which C60 carbons are directly included as a ring member in the crown ring were synthesized for the first time; the UV-Vis absorption spectra were sensitively changed by the addition of metal and ammonium cations.
- Ikeda, Atsushi,Fukuhara, Chie,Shinkai, Seiji
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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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- Synthesis, anti-microbial activity and molecular docking studies on triazolylcoumarin derivatives
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A series of triazolylcoumarins was synthesized by the cycloaddition of acetylenic derivatives to azide in the presence of Cu(I) catalyst at room temperature. All the synthesized compounds were evaluated for their anti-microbial activity against Gram-posit
- Satheeshkumar, Chinnadurai,Ravivarma, Mahalingam,Arjun, Pandian,Silambarasan, Vaithiyanathan,Raaman, Nanjian,Velmurugan, Devadasan,Song, Changsik,Rajakumar, Perumal
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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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- Highly soluble electroactive ethylenedioxythiopene (EDOT)-based copolymer obtained via ‘click’ copolymerization
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Poly (3,4-ethylenedioxythiophene) (PEDOT), in spite of its remarkable attributes, remains insoluble in many common solvents. By adopting the copolymerization approach, a new electroactive polythiopene derivative is synthesized with enhanced solubility by polymerizing an alkyne-functionalized (3-4-ethylenedioxythiophene) (EDOT) and an azide-functionalized tetraethylene glycol via copper catalyzed alkyne-azide cycloaddition (CuAAC). The copolymer, EDOT-co-1,2,3-triazolium, exhibits an interesting chemical structure that makes it an ideal electroactive material. With its polar nature, it readily dissolves in solvents such as DMSO, DMF and PC. Furthermore, the introduction of the oxyethylene monomer as well as the formation of the 1,2,3-triazole during the polymerization step lowers its glass transition temperature inducing a faster switching between its reduced and oxidized state compared to pristine PEDOT.
- Kim, Hern,More, Pawan P.,Puguan, John Marc C.,Rathod, Pramod V.
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- Bis(rhodamine)-based polyether type of turn-on fluorescent sensors: selectively sensing Fe(III)
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Due to the paramagnetic nature of Fe(III), receptor ligand becomes one of the key points in developing fluorescent Fe(III) sensors. We report that a new type of receptor ligands that consist of a polyether capped with two amide groups of N-(rhodamine-6G)l
- Lin, Yang-Lin,Sung, Robert,Sung, Kuangsen
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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 0077-0078
(2021/03/19)
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- Azo high polymer for transporting medicine to intestinal tracts and releasing medicine as well as preparation method and application of azo high polymer
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The invention discloses an azo high polymer for transporting medicine to intestinal tracts and releasing the medicine as well as a preparation method and application of the azo high polymer. The azo high polymer is synthesized by taking dibromoalkane with two brominated ends, oligomeric glycol, paranitroaniline and m-hydroxybenzoic acid as main raw materials. The final structure of the azo high polymer is shown in a formula described in the specifications of the invention; in the formula, x is equal to the sum of y and z, n is equal to 2, 3, 4, 5..., m is equal to 2, 3, 4, 5...; the high polymer can wrap the medicine to form particles through a double emulsification method, the particles reach the intestinal tracts through oral administration, then azo bonds are cut off by bacteria living in the intestinal tracts, the medicine is released, and therefore the effect of treating intestinal diseases is achieved.
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Paragraph 0030; 0034; 0045-0046
(2021/08/21)
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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; 0246-0249
(2021/04/21)
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- COMPOSITIONS AND METHODS RELATED TO MOLECULAR CONJUGATION
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The invention relates to activated Michael acceptor (AMA) compounds that can undergo conjugation with biomolecules containing Michael donor moieties, thereby providing plasma-stable antibody-drug conjugates (ADCs). Pharmaceutical compositions of the ADCs are disclosed as well. Also provided herein are a number of applications (e.g., therapeutic applications) in which the compositions are useful.
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Page/Page column 46; 47
(2021/06/11)
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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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- 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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- 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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- 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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- 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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supporting information
p. 17080 - 17087
(2021/07/02)
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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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- MONOMER AND MULTIMERIC ANTI-HBV AGENTS
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The present invention is directed to compounds, compositions and methods for preventing, treating or curing hepatitis B (HBV) infection in human subjects or other animal hosts. The compounds are as also pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof as pharmaceutical compositions and methods for treatment, prevention or eradication of HBV infection.
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Page/Page column 143; 196-197
(2020/05/15)
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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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(2020/09/13)
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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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- Assisted enzyme replacement therapy
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Reagents and methods useful for the synthesis of conjugates comprising guanidinylated cyclic acetals are provided. Also provided are methods for increasing the cellular uptake of various therapeutic compounds and treatment modalities using these conjugates.
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Page/Page column 93; 95; 96; 97
(2018/03/07)
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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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- Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors
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Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure–activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket.
- McIver, Andrew L.,Zhang, Weihe,Liu, Qingyang,Jiang, Xinpeng,Stashko, Michael A.,Nichols, James,Miley, Michael J.,Norris-Drouin, Jacqueline,Machius, Mischa,DeRyckere, Deborah,Wood, Edgar,Graham, Douglas K.,Earp, H. Shelton,Kireev, Dmitri,Frye, Stephen V.,Wang, Xiaodong
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supporting information
p. 207 - 213
(2017/02/15)
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- Polymeric mannosides prevent DC-SIGN-mediated cell-infection by cytomegalovirus
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Human cytomegalovirus (HCMV) is a beta-herpesvirus with a high prevalence in the population. HCMV is asymptomatic for immunocompetent adults but is a leading cause of morbidity for new born and immunocompromised patients. It was recently shown that the envelope glycoprotein B (gB) of HCMV interacts with the Dendritic Cell-Specific ICAM-3 Grabbing Non integrin (DC-SIGN) to infect the host. In this work we developed a set of DC-SIGN blockers based on mono-, di-, tetra and polyvalent mannosides. The multivalent mannosides were designed to interact with the carbohydrate recognition domains of DC-SIGN in a chelate or bind and recapture process, and represent the first chemical antiadhesives of HCMV reported so far. Polymeric dextrans coated with triazolylheptylmannoside (THM) ligands were highly potent, blocking the gB and DC-SIGN interaction at nanomolar concentrations. The compounds were further assessed for their ability to prevent the DC-SIGN mediated HCMV infection of dendritic cells. A dextran polymer coated with an average of 902 THM ligands showed an outstanding effect in blocking the HCMV trans-infection with IC50 values down to the picomolar range (nanomolar when expressed in THM concentration). Each THM moiety on the polymer surpassed the antiadhesive effect of the methylmannoside reference by more than four orders of magnitude. The compound proved non-cytotoxic at the high concentration of 2 mM and therefore represents an interesting antiadhesive candidate against HCMV and potentially against other virus hijacking dendritic cells to infect the host.
- Brument,Cheneau,Brissonnet,Deniaud,Halary,Gouin
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p. 7660 - 7671
(2017/09/27)
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- Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter
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A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in t
- Steiger, Scott A.,Li, Chun,Backos, Donald S.,Reigan, Philip,Natale
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supporting information
p. 3223 - 3234
(2017/05/29)
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- Chemoproteomics-Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT
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We present a novel chemical scaffold for cysteine-reactive covalent inhibitors. Chloromethyl triazoles (CMTs) are readily accessed in only two chemical steps, thus enabling the rapid optimization of the pharmacological properties of these inhibitors. We d
- Wang, Chao,Abegg, Daniel,Hoch, Dominic G.,Adibekian, Alexander
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supporting information
p. 2911 - 2915
(2016/02/27)
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- Preparation method and application of diazido-substituted poly(tetraethylene glycol)
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The invention provides diazido-substituted poly(tetraethylene glycol), and the structural formula is as follow (please see the formula in the description).The synthesized diazido-substituted poly(tetraethylene glycol) can promote proliferation and migration of fibroblasts and epithelial cells, promote expression of collagen I protein in the cells, stimulate cell factors including NF-kappaB, STAT3, AP1 and Myc which are included in the cells and related to an inflammatory reaction to comprehensively play a role in wound healing promotion and enable the cell factors to achieve the significant treatment effect at the extremely low dosage.Therefore, the diazido-substituted poly(tetraethylene glycol) is likely to change the market pattern of existing wound healing promotion drugs and becomes a clinical drug which can be used for a long term, effectively promote wound healing and improve the healing effect.
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Paragraph 0048; 0049; 0050; 0051; 0052
(2016/10/10)
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- Optimization of the Sensitization Process and Stability of Octadentate Eu(III) 1,2-HOPO Complexes
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The synthesis of a series of octadentate ligands containing the 1-hydroxypyridin-2-one (1,2-HOPO) group in complex with europium(III) is reported. Within this series, the central bridge connecting two diethylenetriamine units linked to two 1,2-HOPO chromophores at the extremities (5-LIN-1,2-HOPO) is varied from a short ethylene chain (H(2,2)-1,2-HOPO) to a long pentaethylene oxide chain (H(17O5,2)-1,2-HOPO). The thermodynamic stability of the europium complexes has been studied and reveals these complexes may be effective for biological measurements. Extension of the central bridge results in exclusion of the inner-sphere water molecule observed for [Eu(H(2,2)-1,2-HOPO)]- going from a nonacoordinated to an octacoordinated Eu(III) ion. With the longer chain length ligands, the complexes display increased luminescence properties in aqueous medium with an optimum of 20% luminescence quantum yield for the [Eu(H(17O5,2)-1,2-HOPO)]- complex. The luminescence properties for [Eu(H(14O4,2)-1,2-HOPO)]- and [Eu(H(17O5,2)-1,2-HOPO)]- are better than that of the model bis-tetradentate [Eu(5LINMe-1,2-HOPO)2]- complex, suggesting a different geometry around the metal center despite the geometric freedom allowed by the longer central chain in the H(mOn,2) scaffold. These differences are also evidenced by examining the luminescence spectra at room temperature and at 77 K and by calculating the luminescence kinetic parameters of the europium complexes. (Graph Presented).
- D'Aléo, Anthony,Moore, Evan G.,Xu, Jide,Daumann, Lena J.,Raymond, Kenneth N.
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p. 6807 - 6820
(2015/08/03)
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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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- ARTICLES AND METHODS COMPRISING PERSISTENT CARBENES AND RELATED COMPOSITIONS
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Articles and methods comprising persistent carbenes are provided, as well as related compositions. In some embodiments, a persistent carbene may be associated with a portion of a substrate (e.g., at least a portion of a surface on the substrate). In certain embodiments, the association of persistent carbene with the substrate may be used to affect certain properties of substrate (e.g., surface chemistry, stability). In some cases, a persistent carbene may be functionalized after association with a portion of a substrate. In some embodiments, a persistent carbene and at least one secondary compound may be associated with a portion of a substrate. Articles and methods of the present invention may be useful for applications involving electronics, sensing, microfabrication, nanotechnology, biomimetic, and drug delivery, amongst others.
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Paragraph 0313
(2014/09/30)
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- A dicationic, podand-like, ionic liquid water system accelerated copper-catalyzed azide-alkyne click reaction
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In this work, an effective, task specific, dicationic, podand-like ionic liquid was synthesized and applied to improve the capability features of click reaction. Moreover, to broaden the scope and decreasing the serious limitations of preparation methods of organic azides, a simple green procedure for the preparation of alkyl azides, the fundamental starting materials in click reactions, from alcohols under solvent-free conditions and microwave irradiation has been reported, for the first time.
- Javaherian, Mohammad,Kazemi, Foad,Ghaemi, Masoumeh
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p. 1643 - 1647
(2015/01/09)
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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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- Specific surface modification of the acetylene-linked glycolipid vesicle by click chemistry
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A novel glycolipid with a terminal acetylene was synthesized and used to prepare unilamellar vesicles. Using these vesicles, a convenient method was developed for the specific modification of the vesicle surface using the photoresponsive copper complex [Cu(OH2)(cage)] as the catalyst for a click reaction.
- Ito, Hidehiro,Kamachi, Toshiaki,Yashima, Eiji
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supporting information; experimental part
p. 5650 - 5652
(2012/07/17)
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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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- Bivalent dopamine D2 receptor ligands: Synthesis and binding properties
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Dopamine D2 receptor homodimers might be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising target proteins for the discovery of atypical antipsychotics. A highly attractive approach to investigate and control GPCR dimerization may be provided by the exploration and characterization of bivalent ligands, which can act as molecular probes simultaneously binding two adjacent binding sites of a dimer. The synthesis of bivalent dopamine D2 receptor ligands of type 1 is presented, incorporating the privileged structure of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAPs) and triazolyl-linked spacer elements. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for bivalent ligands with particular spacer lengths and a comparative analysis with respective monovalent control ligands and unsymmetrically substituted analogues indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.
- Kühhorn, Julia,Hübner, Harald,Gmeiner, Peter
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supporting information; experimental part
p. 4896 - 4903
(2011/09/19)
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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
(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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