- Photoactive chelates for radiolabelling proteins
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Photochemical reactions are an attractive foundation for the synthesis of radiolabelled antibodies, immunoglobulin fragments and other proteins/peptides. The synthesis, 68Ga-radiochemistry and photochemical reactivity of three macrocyclic chela
- Eichenberger, Larissa S.,Patra, Malay,Holland, Jason P.
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Read Online
- Selecting a DNA-Encoded Chemical Library against Non-immobilized Proteins Using a "ligate-Cross-Link-Purify" Strategy
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DNA-encoded chemical libraries (DELs) have recently emerged and become an important technology platform in biomedical research and drug discovery. DELs containing large numbers of compounds can be prepared and selected against biological targets to discov
- Shi, Bingbing,Deng, Yuqing,Zhao, Peng,Li, Xiaoyu
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Read Online
- PHOTOAFFINITY PROBES FOR GIBBERELLIN-BINDING PROTEINS
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A rational approach to the design, synthesis and radiolabelling, with either 3H or 125I, of gibberellin A4 (GA4) derivatives containing C-17-arylazido functionalities is described.The potential of these compounds as photoaffinity rea
- Beale, Michael H.,Hooley, Richard,Smith, Sally J.,Walker, Robert P.
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Read Online
- "clickable" Albumin Binders for Modulating the Tumor Uptake of Targeted Radiopharmaceuticals
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The intentional binding of radioligands to albumin gains increasing attention in the context of radiopharmaceutical cancer therapy as it can lead to an enhanced radioactivity uptake into the tumor lesions and, thus, to a potentially improved therapeutic outcome. However, the influence of the radioligand's albumin-binding affinity on the time profile of tumor uptake has been only partly addressed so far. Based on the previously identified N?-4-(4-iodophenyl)butanoyl-lysine scaffold, we designed "clickable"lysine-derived albumin binders (cLABs) and determined their dissociation constants toward albumin by novel assay methods. Structure-activity relationships were derived, and selected cLABs were applied for the modification of the somatostatin receptor subtype 2 ligand (Tyr3)octreotate. These novel conjugates were radiolabeled with copper-64 and subjected to a detailed in vitro and in vivo radiopharmacological characterization. Overall, the results of this study provide an incentive for further investigations of albumin binders for applications in endoradionuclide therapies.
- Bachmann, Michael,Brandt, Florian,Kopka, Klaus,Laube, Markus,Pietzsch, Jens,Ullrich, Martin,Wodtke, Robert,L?ser, Reik,Pietzsch, Hans-Jürgen,Van Den Hoff, J?rg
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p. 710 - 733
(2022/01/11)
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- Identification of Pyruvate Carboxylase as the Cellular Target of Natural Bibenzyls with Potent Anticancer Activity against Hepatocellular Carcinoma via Metabolic Reprogramming
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Cancer cell proliferation in some organs often depends on conversion of pyruvate to oxaloacetate via pyruvate carboxylase (PC) for replenishing the tricarboxylic acid cycle to support biomass production. In this study, PC was identified as the cellular target of erianin using the photoaffinity labeling-click chemistry-based probe strategy. Erianin potently inhibited the enzymatic activity of PC, which mediated the anticancer effect of erianin in human hepatocellular carcinoma (HCC). Erianin modulated cancer-related gene expression and induced changes in metabolic intermediates. Moreover, erianin promotes mitochondrial oxidative stress and inhibits glycolysis, leading to insufficient energy required for cell proliferation. Analysis of 14 natural analogs of erianin showed that some compounds exhibited potent inhibitory effects on PC. These results suggest that PC is a cellular target of erianin and reveal the unrecognized function of PC in HCC tumorigenesis; erianin along with its analogs warrants further development as a novel therapeutic strategy for the treatment of HCC.
- Chen, Yuwen,Huang, Yulan,Jiao, Wei,Li, Fu,Li, Suiyan,Li, Wenhua,Lin, Yuan,Liu, Wanli,Ma, Yuling,Sheng, Yuwen,Suksamrarn, Apichart,Wang, Fei,Wang, Jing,Wei, Xiao,Wisanwattana, Wisanee,Wu, Wenbi,Zeng, Zhongqiu,Zhang, Guolin,Zhang, Jichao,Zhu, Qiyu
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supporting information
(2022/01/03)
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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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- A Potent Halogen-Bonding Donor Motif for Anion Recognition and Anion Template Mechanical Bond Synthesis
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The covalent attachment of electron deficient perfluoroaryl substituents to a bis-iodotriazole pyridinium group produces a remarkably potent halogen bonding donor motif for anion recognition in aqueous media. Such a motif also establishes halogen bonding anion templation as a highly efficient method for constructing a mechanically interlocked molecule in unprecedented near quantitative yield. The resulting bis-perfluoroaryl substituted iodotriazole pyridinium axle containing halogen bonding [2]rotaxane host exhibits exceptionally strong halide binding affinities in competitive 50 % water containing aqueous media, by a factor of at least three orders of magnitude greater in comparison to a hydrogen bonding rotaxane host analogue. These observations further champion and advance halogen bonding as a powerful tool for recognizing anions in aqueous media.
- Bunchuay, Thanthapatra,Docker, Andrew,Martinez-Martinez, Antonio J.,Beer, Paul D.
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supporting information
p. 13823 - 13827
(2019/08/22)
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- NEW TARGETED CYTOTOXIC RATJADONE DERIVATIVES AND CONJUGATES THEREOF
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The present invention is directed to novel natural product-derived ratjadone-based compounds useful as payloads (or toxins) in drug-conjugates constructs with cell target binding moieties (CTBM) and payload-linker compounds useful in connection with drug conjugates. The present invention further relates to new ratjadone compositions including the aforementioned payloads, payload-linkers and drug conjugates, and methods for using these payloads, payload-linkers and drug conjugates, to treat pathological conditions including cancer, inflammatory and infectious diseases.
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Paragraph 00215; 00216
(2019/02/25)
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- Transient Protection of Organic Azides from Click Reactions with Alkynes by Phosphazide Formation
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A method for protecting organic azides from click reactions with alkynes is reported. Treatment of azides with Amphos affords phosphazides, which are stable under click reaction conditions and are easily converted back to azides by treatment with elemental sulfur. Thus, the method allows for facile modification of azide compounds via site-selective click reactions.
- Meguro, Tomohiro,Yoshida, Suguru,Igawa, Kazunobu,Tomooka, Katsuhiko,Hosoya, Takamitsu
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supporting information
p. 4126 - 4130
(2018/07/15)
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- CHEMOSELECTIVE THIOL-CONJUGATION WITH ALKENE OR ALKYNE-PHOSPHONAMIDATES
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Disclosed are novel conjugates and processes for the preparation thereof. A process for the preparation of alkene- or alkyne-phosphonamidates comprises the steps of (I) reacting a compound of formula (III), with an azide of formula (IV), to prepare a compound of formula (V), reacting a compound of formula (V) with a thiol-containing molecule of formula (VI), resulting in a compound of formula (VII).
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- Identification of Annexin A2 as a target protein for plant alkaloid matrine
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Matrine is a plant alkaloid and a major active component in the Chinese medical herb Sophora flavescens. Matrine has shown potent anti-cancer activities but its molecular target(s) and mechanism are still unknown. Using the photo-affinity labeling approach, for the first time, Annexin A2 was identified as a direct-binding target of matrine in cancer cells.
- Wang, Dongyao,Cao, Yan,Zheng, Leyi,Lv, Diya,Chen, Langdong,Xing, Xinrui,Zhu, Zhenyu,Li, Xiaoyu,Chai, Yifeng
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supporting information
p. 5020 - 5023
(2017/07/11)
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- Target Identification of Kinase Inhibitor Alisertib (MLN8237) by Using DNA-Programmed Affinity Labeling
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Accurate identification of the molecular targets of bioactive small molecules is a highly important yet challenging task in biomedical research. Previously, a method named DPAL (DNA-programmed affinity labeling) for labeling and identifying the cellular targets of small molecules and nucleic acids was developed. Herein, DPAL is applied for the target identification of Alisertib (MLN8237), which is a highly specific aurora kinase A (AKA) inhibitor and a drug candidate being tested in clinical trials for cancer treatment. Apart from the well-established target of AKA, several potential new targets of MLN8237 were identified. Among them, p38 mitogen-activated protein kinase (p38) and laminin receptor (LAMR) were validated to be implicated in the anticancer activities of MLN8237. Interestingly, these new targets were not identified with non-DNA-based affinity probes. This work may facilitate an understanding of the molecular basis of the efficacy and side effects of MLN8237 as a clinical drug candidate. On the other hand, this work has also demonstrated that the method of DPAL could be a useful tool for target identification of bioactive small molecules.
- Wang, Dong-Yao,Cao, Yan,Zheng, Le-Yi,Chen, Lang-Dong,Chen, Xiao-Fei,Hong, Zhan-Ying,Zhu, Zhen-Yu,Li, Xiaoyu,Chai, Yi-Feng
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supporting information
p. 10906 - 10914
(2017/08/22)
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- METHOD FOR CELL MEMBRANE PERMEATION FOR COMPOUND
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The present invention discloses a cell-penetrating method for compounds, comprising the following steps of: (1) preparing raw materials, i.e., the compounds and DNA or RNA; (2) linking: linking the compounds to the DNA or RNA to obtain a molecular conjuga
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Paragraph 0050
(2016/06/28)
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- COMPOUND ADMINISTRATION PRECURSOR AND MEDICAMENT CARRIER PREPARATION
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The present invention provides a compound drug-delivery precursor for membrane permeation, and a drug carrier preparation based on this precursor. The compound drug-delivery precursor and the drug carrier preparation of the present invention may effective
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Paragraph 0061
(2016/06/28)
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- DRUG TARGET CAPTURING METHOD
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The present invention discloses a method for capturing drug targets, comprising the following steps of: (1) preparing row materials, i.e., compounds and DNA or RNA or one party of other specific affinity materials; (2) linking: covalently linking the comp
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Paragraph 0068
(2016/06/28)
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- Generation of cycloheptynes and cyclooctynes via a sulfoxide-magnesium exchange reaction of readily synthesized 2-sulfinylcycloalkenyl triflates
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Cycloheptynes and cyclooctynes were efficiently generated via a sulfoxide-magnesium exchange reaction of readily synthesized 2-sulfinylcycloalkenyl triflates. Cycloadditions between various ynophiles and the cycloalkynes generated by this method proceeded
- Yoshida, Suguru,Karaki, Fumika,Uchida, Keisuke,Hosoya, Takamitsu
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supporting information
p. 8745 - 8748
(2015/05/20)
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- LIGHT-ENABLED DRUG DELIVERY
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Conjugates are provided which comprise a membrane permeable drug linked to a moiety that is not membrane permeable. Attachment of the moiety that is not membrane permeable prevents the drug from crossing cell membranes and entering cells. However, exposure to light either i) breaks the linkage, releasing the drug and allowing it to enter cells; or ii) converts the non-membrane permeable moiety to a membrane permeable form, allowing the entire conjugate to enter the cell, where the drug is released from the conjugate by cleavage. The membrane permeable drugs are thus delivered to cells at locations of interest, e.g. cancer cells in a tumor, in a temporally and spatially controlled manner.
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Paragraph 0119; 0120; 0121; 0122; 0123; 0124
(2014/09/03)
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- CROSS-LINKING ATP ANALOGS
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An adenosine 5′-triphosphate analogs modified at the gamma-phosphate with a reactive reagent. A method of forming the analog by activating a 4-amino benzoic acid, incubating the activated acid to obtain an amine, and coupling the amine with ATP in the presence of water soluble EDCI. A method of detecting the efficacy of a therapeutic by adding a gamma-phosphate modified ATP analog to a protein substrate, reacting the target proteins with the ATP analog, and analyzing the resulting cross-linked product, wherein the amount of product present correlates to the efficacy of the therapeutic is also provided.
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- Photocaged permeability: A new strategy for controlled drug release
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Light is used to release a drug from a cell impermeable small molecule, uncloaking its cytotoxic effect on cancer cells.
- Dcona, M. Michael,Mitra, Deboleena,Goehe, Rachel W.,Gewirtz, David A.,Lebman, Deborah A.,Hartman, Matthew C. T.
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supporting information; experimental part
p. 4755 - 4757
(2012/06/16)
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- Design and synthesis of (+)-discodermolide-paclitaxel hybrids leading to enhanced biological activity
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Potential binding modes of (+)-discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket oc
- Smith, Amos B.,Sugasawa, Keizo,Atasoylu, Onur,Yang, Chia-Ping Huang,Horwitz, Susan Band
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scheme or table
p. 6319 - 6327
(2011/11/06)
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- Phosphorylation-dependent kinase-substrate cross-linking
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"Chemical Equation Presented" Pinning down kinase substrates: The identification of substrates of a particular kinase is fundamental to the elucidation of cell-signaling cascades. This problem has now been addressed by the title approach involving kinase-catalyzed labeling coupled with photo-cross-linking (see scheme). When coupled with mass spectrometry analysis, this strategy can be used to determine the sites of phosphorylation as well as the effector kinase. ADP = adenosine 5'-diphosphate.
- Suwal, Sujit,Pflum, Mary Kay H.
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experimental part
p. 1627 - 1630
(2010/06/15)
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- First synthesis of N-acylated photoactivatable analogues of glutathione bearing an aryl azide moiety
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N-Acylated photoactivatable analogues of glutathione bearing an aryl azide moiety were synthesized for the first time starting from S-tritylglutathione. Georg Thieme Verlag Stuttgart.
- Bernardi, Dan,Ba, Lalla Aicha,Kirsch, Gilbert
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p. 140 - 144
(2008/01/03)
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- Synthesis of novel and photolabile philanthotoxin analogs: Glutamate receptor antagonists
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The synthetic methods for 27 novel and photolabile philanthotoxin analogs are described. Most analogs were synthesized by two general methods with modifications of these methods where necessary.
- Choi,Goodnow,Kalivretenos,Chiles,Fushiya,Nakanishi
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p. 4793 - 4822
(2007/10/02)
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