- Synthesis and photochemical protein crosslinking studies of hydrophilic naphthalimides
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A mixture of 4-alkylamino-1,8-naphthalimides has previously been reported to exhibit potential utility as a photochemical tissue-bonding reagent. In order to determine which constituents of the mixture were responsible for the observed tissue bonding and
- Zhang, Jianxing,Woods, R. Jeremy,Brown, Philip B.,Kap, Duk Lee,Kane, Robert R.
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- Non-natural glycosphingolipids and structurally simpler analogues bind HIV-1 recombinant gp120
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Interactions of recombinant gp120 (rgp120) with non-natural glycosphingolipids (GSLs) and structurally simpler analogues have been studied using a competitive adhesion assay. Conjugates of cellobiosyl ceramide and melibiosyl ceramide were synthetically pr
- McReynolds, Katherine D.,Bhat, Abhijit,Conboy, John C.,Saavedra,Gervay-Hague, Jacquelyn
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- Solution- and solid-phase synthesis of components for tethered bilayer membranes
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The synthesis of the novel compound PhCH2SS(C24H44N4O10) (C20H41) (5) for the preparation of tethered bilayer membranes is described. The compound is the all-amide analogue of the previously reported ester-containing membrane-forming material PhCH2SS(C24H40O14) (C20H41) (1). The advanced intermediate (C20S41) C16H28N3O8 (17) was prepared from the same starting materials using both solution-phase (13% yield) and solid-phase (81% yield) techniques. Monolayers on gold derived from 5 have been analyzed by ellipsometry and FTIR. The monolayers exhibit thicknesses similar to monolayers derived from 1 and possess H-bonded amide functionality.
- Bendavid,Burns,Field,Hashimoto,Ridley,Sandanayake,Wieczorek
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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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- GM1-Binding Conjugates to Improve Intestinal Permeability
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Drugs and proteins with poor intestinal permeability have a limited oral bioavailability. To remediate this problem, a receptor-mediated endocytosis and transcytosis approach was explored. Indeed, the nontoxic β subunit of cholera toxin (CTB) can cross the intestinal barrier by binding to receptor GM1. In this study, we explored the use of GM1-binding peptides and CTB as potential covalent carriers of poorly permeable molecules. GM1-binding peptides (G23, P3) and CTB were conjugated to poorly permeable fluorescent probes such as fluorescein isothiocyanate (FITC) and albumin-FITC using triethylene glycol spacers and click chemistry. The affinity of the peptide conjugates with receptor GM1 was confirmed by isothermal titration calorimetry or microscale thermophoresis, and the results suggested the involvement of nonspecific interactions. Conjugating the model drugs to G23 and P3 improved the internalization into Caco-2 and T84 cells, although the process was not dependent on the amount of GM1 receptor. However, conjugation of bovine serum albumin FITC to CTB increased the internalization in the same cells in a GM1-dependent pathway. Peptide conjugates demonstrated a limited permeability through a Caco-2 monolayer, whereas G23 and CTB conjugates slightly enhanced permeability through a T84 cell monolayer compared to model drugs alone. Since CTB can improve the permeability of large macromolecules such as albumin, it is an interesting carrier for the improvement of oral bioavailability of various other macromolecules such as heparins, proteins, and siRNAs.
- Melkoumov, Alexandre,St-Jean, Isabelle,Banquy, Xavier,Leclair, Grégoire,Leblond Chain, Jeanne
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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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- Target protein degradation inducing compound, preparation method thereof and pharmaceutical composition for preventing or treating targeted protein related diseases containing the same as an active ingredient
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The present invention relates to a degraducer for inducing the decomposition of target protein, a producing method thereof, and a pharmaceutical composition for preventing or treating target protein-related diseases by containing the degraducer as an active ingredient. A novel compound represented by chemical formula 1, ULB-L-PTM, by the present invention, as a degraducer compound inducing the decomposition of target protein using cereblon E3 ubiquitin ligase, is able to significantly achieve a target protein degradation-inducing activity with an excellent binding activity of a cereblon E3 ubiquitin ligase binder thereby, being able to achieve an excellent protein degradation activity by targeting protein or polypeptide related to various diseases. The bromodomain-containing pharmaceutical composition for preventing or treating protein-related diseases or conditions contains the novel compound represented by chemical formula 1 as an active ingredient and has a useful effect of providing a health functional food composition for prevention or improvement.(AA) Example 22 (nM, 24h)COPYRIGHT KIPO 2020
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Paragraph 0943; 0945-0947
(2020/05/01)
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- FUSED HETEROCYCLIC BENZODIAZEPINE DERIVATIVES AND USES THEREOF
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The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
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Page/Page column 126-127; 129
(2020/05/29)
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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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- 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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p. 3671 - 3677
(2020/02/04)
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- NEW THERAPEUTIC VECTORS AND PRODRUGS FOR TREATING CANCERS
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The present invention relates to a compound having the following formula (I) as well as the corresponding prodrugs, pharmaceutical compositions comprising said compounds, in particular for treating cancer.
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Page/Page column 22; 23
(2020/11/22)
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- A MedChem toolbox for cereblon-directed PROTACs
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A modular chemistry toolbox was developed for cereblon-directed PROTACs. A variety of linkers was attached to a CRBN ligand via the 4-amino position of pomalidomide. We used linkers of different constitution to modulate physicochemical properties. We equipped one terminus of the linker with a set of functional groups, e.g. protected amines, protected carboxylic acids, alkynes, chloroalkanes, and protected alcohols, all of which are considered to be attractive for PROTAC design. We also highlight different opportunities for the expansion of the medicinal chemists' PROTAC toolbox towards heterobifunctional molecules, e.g. with biotin, fluorescent, hydrophobic and peptide tags.
- Steinebach, Christian,Sosi?, Izidor,Lindner, Stefanie,Bricelj, Ale?a,Kohl, Franziska,Ng, Yuen Lam Dora,Monschke, Marius,Wagner, Karl G.,Kr?nke, Jan,Gütschow, Michael
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p. 1037 - 1041
(2019/06/27)
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- Optimized reaction pair of the Cyshis tag and Ni(II)-Nta probe for highly selective chemical labeling of membrane proteins
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Chemical labeling of proteins with synthetic molecular probes offers the possibility to probe the functions of proteins of interest in living cells. However, the methods for covalently labeling targeted proteins using complementary peptide tag-probe pairs are still limited, irrespective of the versatility of such pairs in biological research. Herein, we report the new CysHis tag-Ni(II) probe pair for the specific covalent labeling of proteins. A broad-range evaluation of the reactivity profiles of the probe and the CysHis peptide tag afforded a tag-probe pair with an optimized and high labeling selectivity and reactivity. In particular, the labeling specificity of this pair was notably improved compared to the previously reported one. This pair was successfully utilized for the fluorescence imaging of membrane proteins on the surfaces of living cells, demonstrating its potential utility in biological research.
- Zenmyo, Naoki,Tokumaru, Hiroki,Uchinomiya, Shohei,Fuchida, Hirokazu,Tabata, Shigekazu,Hamachi, Itaru,Shigemoto, Ryuichi,Ojida, Akio
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p. 995 - 1000
(2019/07/18)
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- NOVEL BENZODIAZEPINE DERIVATIVES AND USES THEREOF
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The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
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- LINKER-DRUG AND ANTIBODY-DRUG CONJUGATE (ADC) EMPLOYING THE SAME
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A linker-drug represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof is provided. In formula (I), C is a conjugator, L is a linker unit, D is a toxin unit, and n is an integer ranging from 1 to 4. The structure of the conjugator is represented by formula (II). In formula (II), X is a leaving group, each of R1 and R2 is independently a single bond or —NH—, and Z is substituted aryl, heteroaryl, linear alkyl, cycloalkyl, heterocycloalkyl, or a combination thereof. The antibody is conjugated to the linker unit through a cysteine residue of the antibody. An antibody-drug conjugate (ADC) employing the above linker-drug is also provided.
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Paragraph 0173; 0174
(2018/07/05)
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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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- 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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p. 9108 - 9116
(2015/08/03)
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- 6-Aminopenicillanic acid (6-APA) derivatives equipped with anchoring arms
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6-APA derivatives were considered as selective labels for the construction of bifunctional linkers dedicated to the oriented immobilization of proteins on materials. Sulbactam-like compounds (i.e., 6-β-sulfonamido-penam sulfones) and penicillin G - like compounds (i.e., para-substituted 6-β- phenylacetamido-penams) were prepared and tested as irreversible inhibitors of representative β-lactamases and D,D-peptidases, respectively. The activity of the modified antibiotics was preserved despite their substitution with various anchoring arms. The (2-nitro-4,5-dimethoxy)-benzyl esters revealed of particular interest due to their capacity to acylate BlaR-CTD without deprotection.
- Favre, Anna?ck,Grugier, Jér?me,Brans, Alain,Joris, Bernard,Marchand-Brynaert, Jacqueline
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supporting information
p. 10818 - 10826
(2013/01/15)
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- ALANINYL MAYTANSINOL ANTIBODY CONJUGATES
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Linker-drug intermediates of Formula I are conjugated to antibodies to form antibody-drug conjugates where the drug moiety is an N-methylalaninyl-maytansinoid. L is E is n is 2, 3, 4, 5, or 6; m is 2, 3 or 4; and q is 0 or 1.
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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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- GALACTOSE DERIVATIVE, DRUG CARRIER AND MEDICINAL COMPOSITION
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The object of the invention is to provide a novel and useful galactose derivative constituting a drug carrier by which a medicine can be efficiently transferred into the liver, a drug carrier comprising the derivative, and a pharmaceutical composition comprising the carrier and a medicine. The present invention relates to a galactose derivative made up of galactose, a suitable spacer and a certain lipid, a drug carrier comprising the derivative and a cationic lipid, and a pharmaceutical composition comprising the carrier and a medicine (preferably a double strand RNA, a double strand DNA, an oligo nucleic acid) .
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(2010/11/27)
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- SMALL MOLECULE COMPOSITIONS AND METHODS FOR INCREASING DRUG EFFICIENCY USING COMPOSITIONS THEREOF
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In certain embodiments, provided herein are compositions and methods for increasing drug efficiency. The conjugates provided are in certain embodiments, for compositions and methods in treatment of variety of diseases and have the formula 1: D - L - S (1)
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Page/Page column 115
(2008/06/13)
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- Orthogonal, convergent syntheses of dendrimers based on melamine with one or two unique surface sites for manipulation
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An orthogonal, convergent route for the introduction of substoichiometric numbers of latent surface sites into dendrimers based on melamine is used to prepare targets that display one or two Boc-protected amines on the periphery. Asymmetry is the result of the stepwise incorporation of functionalized and unfunctionalized dendrons onto the triazine cores, a highly selective process due to the different reactivities of the substituted triazines. The routes to the dendrons rely on iterative reactions of the growing dendrons with triazine cores and diamine linkers. p-Aminobenzylamine is used as a linking group to avoid functional group interconversions or protecting group manipulations. Addition of the benzylamine group to the monochlorotriazine of the dendron proceeds cleanly leaving a less reactive aniline for subsequent reaction with trichlorotriazine. The routes to these targets proceed in 5 or 6 linear steps (11 or 12 total steps) in 40% overall yield. The unique surface sites can be deprotected and subjected to additional chemistries. Reaction of the monofunctionalized dendrimer with trichlorotriazine yields the desired dimer, a molecule whose increased size is evident from light scattering and tapping mode atomic force microscopy, and corroborated with computation.
- Zhang,Nowlan III,Thomson,Lackowski,Simanek
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p. 8914 - 8922
(2007/10/03)
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- Pd-catalyzed synthesis of a tethered soluble polymeric phosphine ligand
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The use of a Pd-catalyzed phosphine-aryl iodide coupling chemistry to prepare soluble polymeric phosphine ligands is described. The lack of sensitivity of the catalyst to the presence of excess phosphine ligand and the fact that the soluble polymeric phos
- Bergbreiter, David E.,Liu, Yun-Shan,Furyk, Steve,Case, Brenda L.
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p. 8799 - 8802
(2007/10/03)
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