- Synthesis of 5-(carboranylalkylmercapto)-2'-deoxyuridines and 3- (carboranylalkyl)thymidines and their evaluation as substrates for human thymidine kinases 1 and 2
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Derivatives of thymidine containing o-carboranylalkyl groups at the N-3 position and derivatives of 2'-deoxyuridine containing o- carboranylalkylmercapto groups at the C-5 position were synthesized. The alkyl spacers consist of 4-8 methylene units. The sy
- Lunato, Anthony J.,Wang, Jianghai,Woollard, Jeffrey E.,Anisuzzaman, Abul K. M.,Ji, Weihua,Rong, Feng-Guang,Ikeda, Seiichiro,Soloway, Albert H.,Eriksson, Staffan,Ives, David H.,Blue, Thomas E.,Tjarks, Werner
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Read Online
- NOVEL LYSOPHOSPHATIDIC ACID DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a compound that specifically activates an LPA4 receptor, and a pharmaceutical composition containing the same. SOLUTION: This invention relates to a novel lysophosphatidic acid derivative that has an agonistic action on an LPA4 receptor and is useful for the prevention and/or treatment of a disease with angiodysplasia caused by the LPA4 receptor, or a disease associated with angiopathy, or symptoms associated therewith. This invention also relates to a pharmaceutical composition containing the lysophosphatidic acid derivative. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0301-0303
(2021/05/28)
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- Design, Synthesis, and Evaluation of Potent, Selective, and Bioavailable AKT Kinase Degraders
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The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR) signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure–activity relationship (SAR) results have been reported. Through extensive SAR studies on various linkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potent AKT proteolysis targeting chimera (PROTAC) degraders: von Hippel–Lindau (VHL)-recruiting degrader 13 (MS98) and cereblon (CRBN)-recruiting degrader 25 (MS170). These two compounds selectively induced robust AKT protein degradation, inhibited downstream signaling, and suppressed cancer cell proliferation. Moreover, these two degraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders 13 and 25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo.
- Cahuzac, Kaitlyn M.,Chen, Xian,Jin, Jian,Liu, Jing,Parsons, Ramon E.,Shen, Yudao,Wang, Li,Xie, Ling,Xu, Jia,Yu, Xufen
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p. 18054 - 18081
(2021/12/13)
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- One-pot approach to functional nucleosides possessing a fluorescent group using nucleobase-exchange reaction by thymidine phosphorylase
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Herein, we describe β-selective coupling between a modified uracil and a deoxyribose to produce functionalized nucleosides catalyzed by thymidine phosphorylase derived from Escherichia coli. This enzyme mediates nucleobase-exchange reactions to convert unnatural nucleosides possessing a large functional group such as a fluorescent molecule, coumarin or pyrene, linked via an alkyl chain at the C5 position of uracil. 5-(Coumarin-7-oxyhex-5- yn)uracil (C4U) displayed 57.2% conversion at 40% DMSO concentration in 1.0 mM phosphate buffer pH 6.8 to transfer thymidine to an unnatural nucleoside with C4U as the base. In the case of using 5-(pyren-1-methyloxyhex-5-yn)uracil (P4U) as the substrate, TP also could catalyse the reaction to generate a product with a very large functional group at 50% DMSO concentration (21.6% conversion). We carried out docking simulations using MF myPrest for the modified uracil bound to the active site of TP. The uracil moiety of the substrate binds to the active site of TP, with the fluorescent moiety linked to the C5 position of the nucleobase located outside the surface of the enzyme. As a consequence, the bulky fluorescent moiety binding to uracil has little influence on the coupling reaction.
- Hatano, Akihiko,Kurosu, Masayuki,Yonaha, Susumu,Okada, Munehiro,Uehara, Sanae
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supporting information
p. 6900 - 6905
(2013/10/08)
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- Fused ring aziridines as a facile entry into triazole fused tricyclic and bicyclic heterocycles
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The intramolecular dipolar cycloaddition of an azide with an alkyne has provided a useful entry into triazole fused tricyclic heterocycles containing both the triazole ring and the oxazolidin-2-one ring system. The requisite azido-alkynes have been prepared via a two-step sequence from fused ring aziridines. A series of 6-12 membered rings containing both the oxazolidinone and triazole rings have been prepared. These ring systems have been designed as conformationally restrained analogs of RNA-binding oxazolidinones. The Royal Society of Chemistry 2012.
- Fang, Fang,Vogel, Megan,Hines, Jennifer V.,Bergmeier, Stephen C.
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p. 3080 - 3091
(2012/05/07)
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