- Synthesis of azide congeners of preQ1 as potential substrates for tRNA guanine transglycosylase
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PreQ1 (2) is a precursor of queuine (1) that in eubacteria is incorporated into transfer RNA (tRNA) by tRNA guanine transglycosylase (TGT) before being further elaborated into queuine. The queuine modification is unusual and occurs across all eukaryotes and eubacteria with few exceptions, but its function remains unclear. As the modified nucleotide occurs through incorporation of a specially synthesized nucleotide instead of via modification of a genetically encoded base, a study of the sites of modification by prepared probes is possible. We report the synthesis of two novel azide congeners (3,4) of preQ1 for this purpose. The evaluation of their interaction with TGT shows that both probes act as weak competitive inhibitors of guanine exchange of guanine(34) tRNATyr with a Ki of ~70 μM. However, we could not show that these are substrates for TGT-catalyzed incorporation into tRNA. We believe the reason for this is a marked loss of binding due to the azide functionality of 3 and 4 abrogating the possibility of two hydrogen bonds to the carbonyl group of Leu231 and Met260 of TGT, previously observed for the terminal methylene amine of preQ1 by x-ray crystallography.
- Brooks, Allen F.,Garcia, George A.,Showalter, Hollis D.
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Read Online
- SYNTHESIS OF 7-CYANO-7-DEAZAGUANINE, ONE OF THE NUCLEOSIDE Q (QUEUOSINE) PRECURSORS FOR THE POST-TRANSCRIPTIONAL MODIFICATION OF tRNA
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7-Cyano-7-deazaguanine, which is one of the precursors of nucleoside Q (queuosine) biosynthesis, was synthesized from 2-methylthio-6-methoxy-7-methyl-7-diazapurine; methoxymethyl protecting group at 9 position could be removed by transformation to acetoxymethyl group followed by hydrolysis with aq. ammonia.
- Kondo, Tadao,Nakatsuka, Shin-ichi,Goto, Toshio
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Read Online
- COMPOUNDS
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The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is selected from C or N; X is selected from O or S; R1 is selected from hydrogen or methyl; Z is CR2R3, wherein R2 and R3 are each independently selected from hydrogen and (1-5C)alkyl, or R2 and R3 are taken together with the carbon atom to which they are attached to form a cyclopropyl or cyclobutyl ring; Z1 is selected from CR4R5, O, S, C(O) or NR6, wherein R4 and R5 are each independently selected from hydrogen, OH, (1-5C)alkyl and phenyl, or R4 and R5 are taken together with the carbon atom to which they are attached to form a cyclopropyl ring, and R6 is selected from hydrogen and (1-5C)alkyl, provided that one, but not both, of Z and Z1 is CH2.
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(2022/02/09)
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- COMPOUNDS
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The present invention provides a compound of formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein: Y is selected from C or N; X is O; bond a is a single or double bond; x is 1 when a is a single bond and x is 0 when a is a double bond; R1 is selected from hydrogen and methyl; R2 (when present) is selected from hydrogen and methyl; R3 is selected from hydrogen, (1-6C)alkyl and (1-6C)alkyl-phenyl, wherein said phenyl is optionally substituted by one or more (for example 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl and halo (such as chloro and fluoro).
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Page/Page column 26
(2022/02/09)
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- Creation of an Engineered Amide Synthetase Biocatalyst by the Rational Separation of a Two-Step Nitrile Synthetase
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The synthesis of amides through acid and amine coupling is one of the most commonly used reactions in medicinal chemistry, yet still requires atom-inefficient coupling reagents. There is a current demand to develop greener, biocatalytic approaches to amide bond formation. The nitrile synthetase (NS) enzymes are a small family of ATP-dependent enzymes which catalyse the transformation of a carboxylic acid into the corresponding nitrile via an amide intermediate. The Bacillus subtilis QueC (BsQueC) is an NS involved in the synthesis of 7-cyano-7-deazaguanine (CDG) natural products. Through sequence homology and structural analysis of BsQueC we identified three highly conserved residues, which could potentially play important roles in NS substrate binding and catalysis. Rational engineering led to the creation of a NS K163A/R204A biocatalyst that converts the CDG acid into the primary amide, but does not proceed to the nitrile. This study suggests that NSs could be further developed for coupling agent-free, amide-forming biocatalysts.
- Hennessy, Alexis J. A.,Huang, Wenli,Savary, Chloé,Campopiano, Dominic J.
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- Design and Synthesis of Pyrrolo[2,3-d]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate
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Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson’s disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of 18 /CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of 18 gave the 2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino] derivative 32 . Optimization of 32 afforded diastereomeric oxolan-3-yl derivatives 44 and 45 , which demonstrated a favorablein vitroPK profile, although they displayed species disconnects in thein vivoPK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds 44 and 45 demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.
- Williamson, Douglas S.,Smith, Garrick P.,Mikkelsen, Gitte K.,Jensen, Thomas,Acheson-Dossang, Pamela,Badolo, Lassina,Bedford, Simon T.,Chell, Victoria,Chen, I-Jen,Dokurno, Pawel,Hentzer, Morten,Newland, Samantha,Ray, Stuart C.,Shaw, Terry,Surgenor, Allan E.,Terry, Lindsey,Wang, Yikang,Christensen, Kenneth V.
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supporting information
p. 10312 - 10332
(2021/07/26)
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- Synthesis and Anti-HIV Activity of Guanine Modified Fluorinated Acyclic Nucleoside Phosphonate Derivatives
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The preparation of an unprecedented series of nucleobase modified 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) acyclic nucleosides in both their (R) and (S) enantiomerically pure forms is described. The synthesis focuses on a Mitsunobu alkylation reaction t
- Luo, Min,Groaz, Elisabetta,De Jonghe, Steven,Schols, Dominique,Herdewijn, Piet
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- A practical synthesis of archaeosine and its base
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A practical synthetic route to 7-formamidino-7-deazaguanosine (archaeosine), a hypermodified nucleoside observed in archaeal tRNA, has been developed, which involves the addition of hydroxylamine to the cyano group of 7-cyano-7-deazaguanosine (preQ0
- Oka, Natsuhisa,Fukuta, Akane,Ando, Kaori
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p. 5709 - 5714
(2018/08/21)
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- Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers
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IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKKα in cellular signaling, to dissect this from IKKβ and to validate it in its own right as a target in inflammatory diseases.
- Anthony, Nahoum G.,Baiget, Jessica,Berretta, Giacomo,Boyd, Marie,Breen, David,Edwards, Joanne,Gamble, Carly,Gray, Alexander I.,Harvey, Alan L.,Hatziieremia, Sophia,Ho, Ka Ho,Huggan, Judith K.,Lang, Stuart,Llona-Minguez, Sabin,Luo, Jia Lin,McIntosh, Kathryn,Paul, Andrew,Plevin, Robin J.,Robertson, Murray N.,Scott, Rebecca,Suckling, Colin J.,Sutcliffe, Oliver B.,Young, Louise C.,Mackay, Simon P.
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p. 7043 - 7066
(2017/09/07)
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- TREATMENTS FOR AUTOIMMUNE DISEASE
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The invention relates to a novel approach to the treatment of autoimmune diseases, particularly multiple sclerosis.In a further embodiment of the invention there is provided a molecule capable of acting as substrate for the queuine-insertase enzyme comple
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- SUBSTITUTED PYRIMIDINE DERIVATIVES USEFUL IN THE TREATMENT OF AUTOIMMUNE DISEASES
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The present invention describes compounds of formula (I) (I) Wherein: R1 is selected from H and CH3 R2 is selected from H, C4H9 alkyl, C6H13 alkyl and C3H6-
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(2016/07/11)
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- A Single Enzyme Transforms a Carboxylic Acid into a Nitrile through an Amide Intermediate
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The biosynthesis of nitriles is known to occur through specialized pathways involving multiple enzymes; however, in bacterial and archeal biosynthesis of 7-deazapurines, a single enzyme, ToyM, catalyzes the conversion of the carboxylic acid containing 7-carboxy-7-deazaguanine (CDG) into its corresponding nitrile, 7-cyano-7-deazaguanine (preQ0). The mechanism of this unusual direct transformation was shown to proceed via the adenylation of CDG, which activates it to form the newly discovered amide intermediate 7-amido-7-deazaguanine (ADG). This is subsequently dehydrated to form the nitrile in a process that consumes a second equivalent of ATP. The authentic amide intermediate is shown to be chemically and kinetically competent. The ability of ToyM to activate two different substrates, an acid and an amide, accounts for this unprecedented one-enzyme catalysis of nitrile synthesis, and the differential rates of these two half reactions suggest that this catalytic ability is derived from an amide synthetase that gained a new function. Double duty: In bacterial and archeal biosynthesis of 7-deazpurines, a single enzyme, ToyM, catalyzes the two-step conversion of the carboxylic acid 7- carboxy-7-deazaguanine (CDG) into the corresponding nitrile, 7-cyano-7-deazaguanine (preQ0). The mechanism of this unusual direct transformation proceeds via the adenylation of CDG. This activates it to form the amide intermediate 7-amido-7-deazaguanine (ADG), which is in turn activated to form the nitrile.
- Nelp, Micah T.,Bandarian, Vahe
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p. 10627 - 10629
(2015/09/02)
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- Rational Re-engineering of a Transcriptional Silencing PreQ1 Riboswitch
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Re-engineered riboswitches that no longer respond to cellular metabolites, but that instead can be controlled by synthetic molecules, are potentially useful gene regulatory tools for use in synthetic biology and biotechnology fields. Previously, extensive genetic selection and screening approaches were employed to re-engineer a natural adenine riboswitch to create orthogonal ON-switches, enabling translational control of target gene expression in response to synthetic ligands. Here, we describe how a rational targeted approach was used to re-engineer the PreQ1 riboswitch from Bacillus subtilis into an orthogonal OFF-switch. In this case, the evaluation of just six synthetic compounds with seven riboswitch mutants led to the identification of an orthogonal riboswitch-ligand pairing that effectively repressed the transcription of selected genes in B. subtilis. The streamlining of the re-engineering approach, and its extension to a second class of riboswitches, provides a methodological platform for the creation of new orthogonal regulatory components for biotechnological applications including gene functional analysis and antimicrobial target validation and screening. (Graph Presented).
- Wu, Ming-Cheng,Lowe, Phillip T.,Robinson, Christopher J.,Vincent, Helen A.,Dixon, Neil,Leigh, James,Micklefield, Jason
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supporting information
p. 9015 - 9021
(2015/08/03)
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- Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ0)
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A convergent and stereoselective synthesis of chiral cyclopentyl- and cyclohexylamine derivatives of nucleoside Q precursor (PreQ0) has been accomplished. This synthetic route allows for an efficient preparation of 4-substituted analogues with
- Llona-Minguez, Sabin,Mackay, Simon P.
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supporting information
p. 1333 - 1338
(2014/07/22)
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- Synthesis, biological evaluation and docking studies of new pyrrolo[2,3-d] pyrimidine derivatives as Src family-selective tyrosine kinase inhibitors
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In this study, the synthesis and potential enzyme interactions of new Pyrrolo[2,3-d]pyrimidine derivatives along with their inhibitory activity against SFK enzymes such as Fyn, Lyn, Hck, and c-Src were reported. The results indicated that compounds were s
- Dincer, Sebla,Cetin, Kadir Taylan,Onay-Besikci, Arzu,Oelgen, Suereyya
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p. 1080 - 1087
(2013/10/01)
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- Nitrile reductase from Geobacillus kaustophilus: A potential catalyst for a new nitrile biotransformation reaction
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The cloning, expression and characterization of a nitrile reductase (NRed) from the thermophile Geobacillus kaustophilus is reported. The enzyme shows a 12-fold increase in activity in response to a temperature change from 25 °C to 65 °C. The substrate scope regarding its biocatalytic applicability was investigated by testing a range of common nitriles. The narrow substrate range observed for the wild-type enzyme prompted the rational design of GkNRed active site mutants based on a previously published homology model from Bacillus subtilis. The activities of the mutants and the wild-type enzyme were investigated in their structure-function relationship regarding the natural substrate 7-cyano-7-deazaguanine (preQ0) as well as a range of synthesized preQ0-like substrate structures. A distinct dependence of the wild-type enzyme activity on specific structural modifications of the natural substrate was observed. Two non-natural nitriles derived from preQ 0 could be reduced to their corresponding amino compounds. Copyright
- Wilding, Birgit,Winkler, Margit,Petschacher, Barbara,Kratzer, Regina,Glieder, Anton,Klempier, Norbert
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p. 2191 - 2198
(2012/11/06)
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- Synthesis and activity of novel 5-substituted pyrrolo[2,3-d]pyrimidine analogues as pp60c-Src tyrosine kinase inhibitors
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Therapy with receptor tyrosine kinase inhibitors provides an improved treatment option in a number of diseases such as cancer, myocardial infection, osteoporosis, stroke, and neurodegeneration. We have designed, synthesized, and evaluated a series of nove
- Oelgen, Suereyya,Isgoer, Yasemin G.,Coban, Tuelay
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experimental part
p. 113 - 120
(2009/04/04)
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- A short and efficient synthesis of the tRNA nucleosides PreQ0 and archaeosine
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Modified nucleosides in tRNAs play an important role in the translational process. They fine tune the codon-anticodon interactions and they influence the folding and stabilisation of the tRNA structure. Herein, we present a novel synthetic route to the highly modified nucleosides PreQ0 and archaeosine. The synthesis involves coupling of a protected 7-cyano-7- deazaguanosine nucleobase with a TBDMS and isopropylidene protected chloro-ribose unit yielding the PreQ0 nucleoside after deprotection. This PreQ0 nucleoside is then used as the starting material for the synthesis of archaeosine providing the first total synthetic access to this hypermodified RNA nucleoside. The Royal Society of Chemistry 2007.
- Brueckl, Tobias,Klepper, Florian,Gutsmiedl, Katrin,Carell, Thomas
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p. 3821 - 3825
(2008/10/09)
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- Total synthesis of dapiramicin B
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The first total synthesis of dapiramicin B, a nucleoside antibiotic, is described. The characteristic N-glycoside linkage in dapiramicin B was effectively constructed by way of the Pd-catalyzed coupling reaction of a heptopyranosylamine with a bromopyrrol
- Ohno, Hiroyuki,Terui, Takashi,Kitawaki, Takafumi,Chida, Noritaka
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p. 5747 - 5750
(2007/10/03)
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- Robust synthesis and crystal-structure analysis of 7-cyano-7-deazaguanine (PreQ0 base) and 7-(aminomethyl)-7-deazaguanine (PreQ1 base)
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We describe robust and efficient synthetic methods for the synthesis of the preQ0 and preQ1 bases, which are the biosynthetic precursors of the hypermodified RNA nucleoside queuosine. The X-ray crystal-structure analysis of preQ1 is also described.
- Klepper, Florian,Polborn, Kurt,Carell, Thomas
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p. 2610 - 2616
(2007/10/03)
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- Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines
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Classical and nonclassical isosteric C8-N9 bridged analogues of the multitargeted antifolate LY231514 were synthesized as inhibitors of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and as antitumor and antiopportunistic infection agents. The
- Gangjee,Vidwans,Elzein,McGuire,Queener,Kisliuk
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p. 1993 - 2003
(2007/10/03)
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- A two step synthesis of the nucleoside Q precursor 2-amino-5-cyanopyrrolo[2,3-d]pyrimidin-4-one (preQ(o))
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PreQ(o) (1) is prepared in a 70% yield by the condensation of chloro(formyl)acetonitrile (2) with 2,6-diaminopyrimidin-4-one (3), and subsequently converted to its amide derivative 5. Isolation of the intermediate 4 in the condensation reaction was also observed giving further insight into the proposed mechanism.
- Migawa, Michael T.,Hinkley, Jack M.,Hoops, Geoffrey C.,Townsend, Leroy B.
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p. 3317 - 3322
(2007/10/03)
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