- 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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- 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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- HETEROCYCLIC DERIVATIVES
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Compounds of the formula (I): Q1-Q2-Q3, in which Q1, Q2 and Q3 have the meanings indicated in Claim 1, degrade target proteins, and can be employed, inter alia, for the treatment of diseases such as cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.
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Page/Page column 52; 79-80
(2020/08/13)
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- Solid-phase synthesis of a novel phalloidin analog with on-bead and off-bead actin-binding activity
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Specific effectors of actin polymerization have found use as dynamic probes of cellular morphology that may be used to gauge cellular response to stimuli and drugs. Of various natural products that target actin, phalloidin is one of the most potent and selective inhibitors of actin depolymerization. Phalloidin and related members of the phallotoxin family are macrocyclic heptapeptides bearing a characteristic and rigidifying transannular tryptathionine bridge. Here we describe a solid-phase synthesis of a new phalloidin analog as a prototype for library development with the potential for on- and off-bead screening. To validate our method, we labelled the phalloidin derivative with a fluorescent dye which stained actin in CHO cells. Furthermore, a bioassay was developed allowing actin polymerization on beads carrying a phalloidin derivative.
- Blanc, Antoine,Todorovic, Mihajlo,Perrin, David M.
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supporting information
p. 385 - 388
(2019/01/09)
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- Cross-linked cyclic porphyrin derivative and method for preparing the same
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The present invention relates to a cross-linked cyclic porphyrin derivative and to a manufacturing method thereof. By using the crosslinked cyclic porphyrin derivative, it is possible to measure a change in color selectively when cations and anions are present together, and thus the cations and the anions, preferably Li cations and halogen anions, can be selectively detected without any separate labels.COPYRIGHT KIPO 2018
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Paragraph 0105; 0126-0130
(2018/07/07)
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- PHENYL TETRAHYDROISOQUINOLINE COMPOUND SUBSTITUTED WITH HETEROARYL
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The present invention provides a compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof which has an excellent NHE3 inhibitory effect: ????????[Formula 15]?????A-Y [1] wherein A represents a structure represented b
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Paragraph 0307
(2017/06/29)
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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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p. 3294 - 3302
(2016/09/09)
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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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- 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 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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- Synthesis and evaluation of homo-bivalent GnRHR ligands
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G protein coupled receptors (GPCRs) are important drug targets in pharmaceutical research. Traditionally, most research efforts have been devoted towards the design of small molecule agonists and antagonists. An interesting, yet poorly investigated class of GPCR modulators comprise the bivalent ligands, in which two receptor pharmacophores are incorporated. Here, we set out to develop a general strategy for the synthesis of bivalent compounds that are projected to bind to the human gonadotropin-releasing hormone receptor (GnRHR). Our results on the dimerisation of a known GnRHR antagonist, with as key step the Huisgen 1,3-cycloaddition, and their ability to bind to and antagonize GnRH-induced GnRHR stimulation, are presented here.
- Bonger, Kimberly M.,van den Berg, Richard J.B.H.N.,Heitman, Laura H.,IJzerman, Ad P.,Oosterom, Julia,Timmers, Cornelis M.,Overkleeft, Herman S.,van der Marel, Gijsbert A.
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p. 4841 - 4856
(2008/03/12)
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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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p. 407 - 408
(2007/10/03)
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