- Synthesis of Galactosyl-Queuosine and Distribution of Hypermodified Q-Nucleosides in Mouse Tissues
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Queuosine (Q) is a hypermodified RNA nucleoside that is found in tRNAHis, tRNAAsn, tRNATyr, and tRNAAsp. It is located at the wobble position of the tRNA anticodon loop, where it can interact with U as well as C bases located at the respective position of the corresponding mRNA codons. In tRNATyr and tRNAAsp of higher eukaryotes, including humans, the Q base is for yet unknown reasons further modified by the addition of a galactose and a mannose sugar, respectively. The reason for this additional modification, and how the sugar modification is orchestrated with Q formation and insertion, is unknown. Here, we report a total synthesis of the hypermodified nucleoside galactosyl-queuosine (galQ). The availability of the compound enabled us to study the absolute levels of the Q-family nucleosides in six different organs of newborn and adult mice, and also in human cytosolic tRNA. Our synthesis now paves the way to a more detailed analysis of the biological function of the Q-nucleoside family.
- Carell, Thomas,Ensfelder, Timm T.,Heiss, Matthias,Hillmeier, Markus,Kellner, Stefanie,Müller, Markus,Michalakis, Stylianos,Sch?n, Alexander,Scheel, Constanze,Thumbs, Peter,Wagner, Mirko
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p. 12352 - 12356
(2020/04/27)
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- Genetic Code Expansion Facilitates Position-Selective Labeling of RNA for Biophysical Studies
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Nature relies on reading and synthesizing the genetic code with high fidelity. Nucleic acid building blocks that are orthogonal to the canonical A-T and G-C base-pairs are therefore uniquely suitable to facilitate position-specific labeling of nucleic aci
- G?bel, Michael,Gr??l, Sylvester,Hegelein, Andreas,Hengesbach, Martin,Müller, Diana,Schwalbe, Harald
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- EC144 is a potent inhibitor of the heat shock protein 90
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Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl) methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that completed phase II clinical trials. Alkyne 40 is more potent than 14 in an Hsp90α binding assay (IC50 = 1.1 vs 5.1 nM) as well as in its ability to degrade Her-2 in MCF-7 cells (EC 50 = 14 vs 38 nM). In a mouse model of gastric tumors (N87), 40 stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qd× 5). Under the same conditions, 14 stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne 40 is approximately 20-fold more efficacious than 14 in mice.
- Shi, Jiandong,Van De Water, Ryan,Hong, Kevin,Lamer, Ryan B.,Weichert, Kenneth W.,Sandoval, Cristina M.,Kasibhatla, Srinivas R.,Boehm, Marcus F.,Chao, Jianhua,Lundgren, Karen,Timple, Noelito,Lough, Rachel,Ibanez, Gerardo,Boykin, Christina,Burrows, Francis J.,Kehry, Marilyn R.,Yun, Theodore J.,Harning, Erin K.,Ambrose, Christine,Thompson, Jeffrey,Bixler, Sarah A.,Dunah, Anthone,Snodgrass-Belt, Pamela,Arndt, Joseph,Enyedy, Istvan J.,Li, Ping,Hong, Victor S.,McKenzie, Andres,Biamonte, Marco A.
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p. 7786 - 7795
(2012/11/07)
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- REAGENTS FOR REVERSIBLY TERMINATING PRIMER EXTENSION
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This invention relates to the field of nucleic acid chemistry, more specifically to the field of compositions of matter that comprise triphosphates of modified 2'-deoxynucleosides and oligonucleotides that are formed when these are appended to the 3'-end of a primer, wherein said modifications comprise NH2 moiety attached to their 3'-hydroxyl group and a fluorescent species in a form of a tag affixed to the nucleobase via a linker that can be cleaved. Such compositions and their associated processes enable and improve the sequencing of oligonucleotides using a strategy of cyclic reversible termination, as outlined in US Patent 6,664,079. Most specifically, the invention concerns compositions of matter that are 5'-triphosphates of ribo- and 2'- deoxyribonucleosides carrying detectable tags and oligonucleotides that might be derived from them. The invention also concerns processes wherein a DNA polymerase, RNA polymerase, or reverse transcriptase synthesizes said oligonucleotides via addition of said triphosphates to a primer.
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Page/Page column 33
(2010/11/04)
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- Synthesis of the transfer-RNA nucleoside queuosine by using a chiral allyl azide intermediate
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Chilled out: Chiral allyl azides are rarely used in natural product synthesis because of their tendency to undergo a [3.3] sigmatropic rearrangement (see scheme, top). In allylic cyclopentenyl azides, this rearrangement can be suppressed at just 0°C, enabling a short convergent synthesis of the hypermodified transfer-RNA nucleoside queuosine. (Chemical Equation Presented).
- Klepper, Florian,Jahn, Eva-Maria,Hickmann, Volker,Carell, Thomas
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p. 2325 - 2327
(2008/03/11)
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- ALKYNYL PYRROLOPYRIMIDINES AND RELATED ANALOGS AS HSP90-INHIBITORS
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Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs are described and demonstrated to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents used in the treatment and prevention of various HSP90 mediated disorders. Methods of synthesis and use of such compounds are also described and claimed.
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Page/Page column 83-84
(2010/11/24)
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- Regioselective syntheses of 7-halogenated 7-deazapurine nucleosides related to 2-amino-7-deaza-2′-deoxyadenosine and 7-deaza-2′- deoxyisoguanosine
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The syntheses of 7-halogenated derivatives 3b-e of 2-amino-7-deaza- 2′-deoxyadenosine as well as 7-bromo and 7-chloro-7-deaza-2′- deoxyisoguanosines 4b-c are described. Nucleobase anion glycosylation was employed for the convergent nucleoside synthesis. T
- Seela, Frank,Peng, Xiaohua
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p. 1203 - 1210
(2007/10/03)
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- Design, synthesis, and biological activities of classical N-{4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl}-L-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and
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Two novel analogues, N-{2-amino-4-ethyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acid (2) and N-{2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl}-L-glutamic acid (4), were designed and synthesized as potent dual inhibi
- Gangjee, Aleem,Yu, Jianming,Kisliuk, Roy L.,Haile, William H.,Sobrero, Giulia,McGuire, John J.
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p. 591 - 600
(2007/10/03)
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- Sugar-modified 7-deaza-7-substituted oligonucleotides
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Functionalized nucleomonomers and oligonucleotides are provided which have increased nuclease resistance and enhanced binding affinity to target DNA or RNA molecules. The oligonucleotides of the present invention comprise at least one 7-deaza-7-iodo-2'-su
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- Positioning of functionalities in a heteroduplex major groove: Synthesis of 7-deaza-2-amino-2'-deoxyadenosines
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We have synthesized the 7-iodo-, 7-cyano- and 7-propynyl-7-deaza-2- amino-2'-deoxyadenosines and incorporated each into several oligonucleotide (ODN) sequences. These oligonucleotides exhibit enhanced binding affinities to RNA complements relative to unmo
- Balow, Guity,Brugger, John,Lesnik, Elena,Acevedo, Oscar L.
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p. 941 - 944
(2007/10/03)
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- THE SYNTHESIS OF N-PYRIMIDIN-5-YL)ETHYL>BENZOYL>-L-GLUTAMIC ACIDS AS ANTINEOPLASTIC AGENTS
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A series of N-pyrimidin-5-yl)ethyl>benzoyl>-L-glutamic acids were synthesized.In this current synthesis, compound 2-amino-4-chloro-pyrrolopyrimidine (4) was selected as an important precursor for the preparation of key intermediates such as 5b, 10b, 15a and 15b.These highly functionalized pyrrolopyrimidines were then later coupled with either 4-ethynylbenzoylglutamate or 4-iodobenzoylglutamate in a palladium catalyzed Heck reaction and thus provided the basic skeleton of the targeted molecules.The availability ofthe chlorine atom at the 4-position of the pyrrolopyrimidine nucleus has allowed us to introduce different substituents at this position efficiently.By this approach, we were able to prepare a variety of 4-substituted pyrrolopyrimidine based folate antagonists (2a-2g) which are closely related to the novel thymidylate synthase inhibitor LY231514.In vitro analysis has demonstrated that some of these agents are highly cytotoxic against human leukemic cells (CCRF-CEM) in culture.
- Shih, Chuan,Gossett, L. S.
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p. 825 - 841
(2007/10/02)
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