- Potent SARS-CoV-2 mRNA Cap Methyltransferase Inhibitors by Bioisosteric Replacement of Methionine in SAM Cosubstrate
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Viral mRNA cap methyltransferases (MTases) are emerging targets for the development of broad-spectrum antiviral agents. In this work, we designed potential SARS-CoV-2 MTase Nsp14 and Nsp16 inhibitors by using bioisosteric substitution of the sulfonium and amino acid substructures of the cosubstrate S-adenosylmethionine (SAM), which serves as the methyl donor in the enzymatic reaction. The synthetically accessible target structures were prioritized using molecular docking. Testing of the inhibitory activity of the synthesized compounds showed nanomolar to submicromolar IC50 values for five compounds. To evaluate selectivity, enzymatic inhibition of the human glycine N-methyltransferase involved in cellular SAM/SAH ratio regulation was also determined, which indicated that the discovered compounds are nonselective inhibitors of the studied MTases with slight selectivity for Nsp16. No cytotoxic effects were observed; however, this is most likely a result of the poor cell permeability of all evaluated compounds.
- Bobi?eva, Olga,Bobrovs, Raitis,Ka?epe, Iveta,Patetko, Liene,Kalni??, Gints,?i?ovs, Mihails,Bula, Anna L.,Grī Nberga, Solveiga,Borodu??is, Mā Rti??,Ramata-Stunda, Anna,Rostoks, Nils,Jirgensons, Aigars,Tā Rs, Kaspars,Jaudzems, Kristaps
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- Synthesis of 5'-N-(2-[18F]Fluoroethyl)-carboxamidoadenosine: A promising tracer for investigation of adenosine receptor system by PET technique
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5'-N-(2-[18F]Fluoroethyl)-carboxainidoadenosine ([18F]FNECA), a promising 18F-labelled adenosine agonist has been prepared by two different synthetic routes. In the first, [18F]fluoride was reacted with 5'-N,N-ethylene-2',3'-O-isopropylidenecarboxamido-adenosine and after removing the protective group [18F]FNECA was obtained in a low radiochemical yield (1 ± 1%, mean ± sd, n = 7, decay corrected). In the second, 2-[18F]fluoroethylamine was synthesised according to the literature and reacted with 2',3'-O-isopropylideneadenosine-5'-uronic acid in the presence of a coupling agent. The following hydrolysis step provided the [18F]FNECA with a modest radiochemical yield (24 ± 9%, n = 17, based on [18F]fluoride-activity). After purification by preparative reverse phase HPLC 18.9-166.5 MBq (0.51-4.5 mCi) [18F]FNECA was obtained with a specific activity of 2.35 ± 1.14 TBq/mmol (63.5 ± 30.9 Ci/mmol, n = 3). The total synthesis took 200 min and the decay corrected radiochemical yield based on [18F]F- activity was 17 ± 9% (n = 5) with more than 99.9% radiochemical purity. This second route provides sufficient [18F]FNECA for the subsequent biological evaluation using PET-technique.
- Lehel,Horvath,Boros,Mikecz,Marian,Szentmiklosi,Tron
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- Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification
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5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine (Bio-AMS, 1) possesses selective activity against Mycobacterium tuberculosis (Mtb) and arrests fatty acid and lipid biosynthesis through inhibition of the Mycobacterium tuberculosis biotin protein ligase (MtBPL). Mtb develops spontaneous resistance to 1 with a frequency of at least 1 × 10-7 by overexpression of Rv3406, a type II sulfatase that enzymatically inactivates 1. In an effort to circumvent this resistance mechanism, we describe herein strategic modification of the nucleoside at the 5′-position to prevent enzymatic inactivation. The new analogues retained subnanomolar potency to MtBPL (KD = 0.66-0.97 nM), and 5′R-C-methyl derivative 6 exhibited identical antimycobacterial activity toward: Mtb H37Rv, MtBPL overexpression, and an isogenic Rv3406 overexpression strain (minimum inhibitory concentration, MIC = 1.56 μM). Moreover, 6 was not metabolized by recombinant Rv3406 and resistant mutants to 6 could not be isolated (frequency of resistance -10) demonstrating it successfully overcame Rv3406-mediated resistance.
- Bockman, Matthew R.,Engelhart, Curtis A.,Dawadi, Surendra,Larson, Peter,Tiwari, Divya,Ferguson, David M.,Schnappinger, Dirk,Aldrich, Courtney C.
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- Tethering small molecules to a phage display library: Discovery of a selective bivalent inhibitor of protein kinase A
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We report a noncovalent tethering methodology for the fragment-based selection of bivalent ligands targeting protein kinases. In this approach, a small-molecule warhead, staurosporine, directs a phage display cyclic peptide library to the active site of cAMP-dependent protein kinase (PKA), allowing for targeted library enrichment. A cyclic peptide discovered through this selection, when covalently attached to a staurosporine derivative, displayed a 90-fold increase in affinity for PKA. Moreover, the bivalent inhibitor was shown to be significantly more selective than the starting warhead when tested against a small panel of kinases. Thus our general methodology allows for covalent linkage of known small-molecule ligands to biological libraries for discovering potent bivalent inhibitors of biological targets. Copyright
- Meyer, Scott C.,Shomin, Carolyn D.,Gaj, Thomas,Ghosh, Indraneel
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- Deamination of 2′,3′-O-isopropylideneadenosine-5′- carboxylic acid catalyzed by adenosine deaminase (ADA) and adenylate deaminase (AMPDA): Influence of substrate ionization on the activity of the enzymes
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Adenosine deaminase (ADA) and adenylate deaminase (AMPDA) catalyze the deamination of 2′,3′-O-isopropylideneadenosine-5′-carboxylic acid to the corresponding inosine derivative and dependence of the rate of enzymatic reaction on the ionization degree of the substrate has been studied at different pH values. Copyright Taylor & Francis Group, LLC.
- Ciuffreda, Pierangela,Alessandrini, Laura,Pavlovic, Radmila,Santaniello, Enzo
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- Monoclonal Antibodies for the Detection of a Specific Cyclic DNA Adduct Derived from ω-6 Polyunsaturated Fatty Acids
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Lipid peroxidation of polyunsaturated fatty acids (PUFAs) is an endogenous source of α,β-unsaturated aldehydes that react with DNA producing a variety of cyclic adducts. The mutagenic cyclic adducts, specifically those derived from oxidation of ω-6 PUFAs, may contribute to the cancer promoting activities associated with ω-6 PUFAs. (E)-4-Hydroxy-2-nonenal (HNE) is a unique product of ω-6 PUFAs oxidation. HNE reacts with deoxyguanosine (dG) yielding mutagenic 1,N2-propanodeoxyguanosine adducts (HNE-dG). Earlier studies showed HNE can also be oxidized to its epoxide (EH), and EH can react with deoxyadenosine (dA) forming the well-studied ?dA and the substituted etheno adducts. Using a liquid chromatography-based tandem mass spectroscopic (LC-MS/MS) method, we previously reported the detection of EH-derived 7-(1′,2′-dihydroxyheptyl)-1,N6-ethenodeoxyadenosine (DHH?dA) as a novel endogenous background adduct in DNA from rodent and human tissues. The formation, repair, and mutagenicity of DHH?dA and its biological consequences in cells have not been investigated. To understand the roles of DHH?dA in carcinogenesis, it is important to develop an immuno-based assay to detect DHH?dA in cells and tissues. In this study we describe the development of monoclonal antibodies specifically against DHH?dA and its application to detect DHH?dA in human cells.
- Dyba, Marcin,Da Silva, Brandon,Coia, Heidi,Hou, Yanqi,Noguchi, Sumire,Pan, Jishen,Berry, Deborah,Creswell, Karen,Krzeminski, Jacek,Desai, Dhimant,Amin, Shantu,Yang, David,Chung, Fung-Lung
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- A METTL3 inhibitor for repairing corneal damage and its drug application
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The present invention discloses a METTL3 inhibitor for repairing corneal damage and pharmaceutical application thereof, the METTL3 inhibitor is a compound shown in formula (I) or a tautomer thereof, a racemic, a racemate, an enantiomer and an diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof. METTL3 inhibitors of the present invention for repairing corneal damage. The present invention provides a small molecule compound capable of inhibiting the activity of the METTL3 protein to play a role in repairing corneal damage and its pharmaceutical applications, specifically the application of organic small molecules based on the structure of the METTL3 protein and related drugs. Compounds disclosed in the present invention are a potent METTL3 inhibitor, the compound is capable of inhibiting the formation of m6A modifications very well. Experiments in the present invention can be concluded that the compounds disclosed in the present invention may play a good corneal repair effect by inhibiting the METTL3 protein.
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Paragraph 0022; 0035-0041
(2022/02/24)
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- Biomarkers for Carcinogenesis and Uses Thereof
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Provided herein are methods of reducing the recurrence of liver cancer in a subject.
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Paragraph 0022; 0085
(2019/08/02)
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- Investigation on 2′,3′- O-Substituted ATP Derivatives and Analogs as Novel P2X3 Receptor Antagonists
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Antagonists of the purinergic P2X3 receptors represent promising drugs for the treatment of inflammation and pain. The ATP derivative 2′,3′-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) has been described as a potent competitive inhibitor of this receptor. In th
- Dal Ben, Diego,Buccioni, Michela,Lambertucci, Catia,Marucci, Gabriella,Spinaci, Andrea,Marchenkova, Anna,Abdelrahman, Aliaa,Nistri, Andrea,Müller, Christa E.,Volpini, Rosaria
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supporting information
p. 493 - 498
(2019/04/25)
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- A selective inhibitor of the UFM1-activating enzyme, UBA5
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Protein conjugation with ubiquitin and ubiquitin-like small molecules, such as UFM1, is important for promoting cancer cell survival and proliferation. Herein, the development of the first selective micromolar inhibitor of the UBA5 E1 enzyme that initiates UFM1 protein conjugation is described. This organometallic inhibitor incorporates adenosine and zinc(II)cyclen within its core scaffold and inhibits UBA5 noncompetitively and selectively over other E1 enzymes and a panel of human kinases. Furthermore, this compound selectively impedes the cellular proliferation (above 50?μM) of cancer cells containing higher levels of UBA5. This inhibitor may be used to further probe the intracellular role of the UFM1 pathway in disease progression.
- da Silva, Sara R.,Paiva, Stacey-Lynn,Bancerz, Matthew,Geletu, Mulu,Lewis, Andrew M.,Chen, Jijun,Cai, Yafei,Lukkarila, Julie L.,Li, Honglin,Gunning, Patrick T.
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supporting information
p. 4542 - 4547
(2016/08/24)
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- UBA5 INHIBITORS
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The present disclosure relates to compounds of the Formula (I), which are UBA5 inhibitors.
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Paragraph 00107; 00112; 00113
(2015/12/18)
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- Mechanistic studies of the radical S-adenosylmethionine enzyme DesII with TDP-D-fucose
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DesII is a radical S-adenosylmethionine (SAM) enzyme that catalyzes the C4-deamination of TDP-4-amino-4,6-dideoxyglucose through a C3 radical intermediate. However, if the C4 amino group is replaced with a hydroxy group (to give TDP-quinovose), the hydroxy group at C3 is oxidized to a ketone with no C4-dehydration. It is hypothesized that hyperconjugation between the C4 C-N/O bond and the partially filled p orbital at C3 of the radical intermediate modulates the degree to which elimination competes with dehydrogenation. To investigate this hypothesis, the reaction of DesII with the C4-epimer of TDP-quinovose (TDP-fucose) was examined. The reaction primarily results in the formation of TDP-6-deoxygulose and likely regeneration of TDP-fucose. The remainder of the substrate radical partitions roughly equally between C3-dehydrogenation and C4-dehydration. Thus, changing the stereochemistry at C4 permits a more balanced competition between elimination and dehydrogenation.
- Ko, Yeonjin,Ruszczycky, Mark W.,Choi, Sei-Hyun,Liu, Hung-Wen
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supporting information
p. 860 - 863
(2015/03/05)
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- 8-Substituted, syn-Configured Adenosine Derivatives as Potential Inhibitors of the Enzyme IspE from the Non-Mevalonate Pathway of Isoprenoid Biosynthesis
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The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are attractive targets for drugs against various diseases, including malaria. We describe herein the structure-based design, synthesis, conformational analysis, and biological evaluation of several 8-brominated or 8-aminated adenosine derivatives with different substituents at C(5′), targeting the ATP-adenine binding site of the IspE protein from the non-mevalonate pathway. An exhaustive conformational analysis of the adenosine derivatives both in solution and in the solid state confirmed the desired syn orientation of the adenine moiety. Despite this favorable pre-organization for binding to the cofactor pocket, biological evaluation of the inhibitors showed only a very modest inhibitory activity.
- Harder, Michael,Sch?fer, Elisabeth,Kümin, Tobias,Illarionov, Boris,Bacher, Adelbert,Fischer, Markus,Diederich, Fran?ois,Bernet, Bruno
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p. 7276 - 7286
(2015/11/25)
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- Synthesis of novel Peptidyl adenosine antibiotic analogs
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A small library of peptidyl adenosine antibiotic analogs was synthesized, under the Pilot Scale Library Program of the NIH Roadmap initiative, from 2′,3′-O-isoproylideneadenosine-5′-carboxylic acid 2 in excellent yield. The coupling of the amino terminus
- Moukha-Chafiq, Omar,Reynolds, Robert C.
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- Comparative inhibitory activity of 3′- and 5′-functionalized nucleosides on ribonuclease A
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Modified nucleosides, molecules, functionalized with various polar groups at different positions have been synthesized to rationalize the impact of structural modification on their inhibitory activity. Agarose gel and precipitation assays indicate their improved inhibitory activity on ribonuclease A (RNase A). Kinetic experiments clearly categorize them as competitive inhibitors of RNase A with improved inhibition constant (Ki) values (37 ± 9, 67 ± 6, and 193±7 μM for compounds 10, 3, and 7, respectively). The preferential hydrogen bonding network formation between His-12 and His-119 of RNase A with the polar carboxylic and amino groups of these compounds has been evidenced from the docking studies. The relationship between structural modifications and inhibitory activity of these compounds is further justified in terms of energetics using PEARLS.
- Debnath, Joy,Dasgupta, Swagata,Pathak, Tanmaya
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experimental part
p. 8257 - 8263
(2011/02/22)
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- Synthesis and biological evaluation of novel neamine-nucleoside conjugates potentially targeting to RNAs
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Eighteen novel neamine-nucleoside conjugates with ethylenediamine-lysine or ethylenediamine-arginine as the linker were synthesized and their potential binding to A site of 16S RNA and TAR RNA was evaluated using SPR (surface plasmon resonance). Compared with neamine, compounds 10i and 10q show 6.3 and 4.8 times potential in binding to A site of 16S RNA and eight and six times potential in binding to TAR RNA, respectively. According to the data of SPR, it indicates that amino acid residue and nucleobase moieties of the designed neamine-nucleosides conjugates exhibit the important contributions for the binding to A site of 16S RNA and TAR RNA. The molecular docking study on the interaction between the ligands and A site of 16S RNA is in agreement with the experimental data. The novel type of modification may provide a promising way for the development of neamine derivatives effectively targeting to RNAs.
- Xu, Yanli,Jin, Hongwei,Yang, Zhenjun,Zhang, Liangren,Zhang, Lihe
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experimental part
p. 5228 - 5239
(2009/12/04)
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- TETRAHYDRO-FURO`3,4-D!DIOXOLE COMPOUNDS AND COMPOSITIONS AND METHOD FOR INHIBITING PLATELET AGGREGATION
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This invention is directed to a method of preventing or treating diseases or conditions associated with platelet aggregation. The method is also directed to a method of treating thrombosis or related disorders. The method comprises administering to a subject a pharmaceutical composition comprising an effective amount of a non-nucleotide compound, preferably a P2Y12 receptor antagonist compound, wherein said amount is effective to inhibit platelet aggregation. The compounds useful for this invention include compounds of general Formulae I and III-XI, or salts, hydrates, and solvates thereof. The present invention also provides novel compounds according to Formulae I and III-XI.
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Page/Page column 62
(2008/06/13)
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- NON-NUCLEOTIDE COMPOSITIONS AND METHOD FOR TREATING PAIN
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The present invention is directed to a method of treating pain. The method comprises administering to a subject a pharmaceutical composition comprising an effective amount of a P2X receptor antagonist. The methods of the present invention are useful in reducing pain, such as traumatic pain, neuropathic pain, organ pain and/or pain associated with diseases. The P2X receptor antagonists useful for this invention are non-nucleotide compounds of general Formula I. Compounds of Formula I can be used alone to treat pain. Compounds of Formula I can also be used in conjunction with other therapeutic agents or adjunctive therapies commonly used to treat pain, thus enhancing the therapeutic effect of pain reduction.
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Page/Page column 60
(2008/06/13)
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- NOVEL ADENOSINE A3 RECEPTOR AGONISTS
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The invention realizes that a series of sulfonamido derivatives with a conserved uronamide group at the 5' position provide superior A3 receptor affinity as well as selectivity. These new adenosine agonists are sulfonamido deritatives N-substituted with aliphatic groups (cyclic or linear) or aromatic radicals.
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Page/Page column 25
(2008/06/13)
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- An improved approach to the synthesis of adenosine-5'-N-ethyluronamides of interest as adenosine receptor agonists
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Adenosine-5'-N-ethyluronamides which are modified at the 6-amino group are of considerable interest as adenosine receptor agonists. This report describes a new and efficient approach to the synthesis of this class of biologically active compounds.
- Ha,Nair
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p. 1567 - 1570
(2007/10/03)
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- Passive Template Effects and Active Acid - Base Involvement in Catalysis of Organic Reactions
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A series of receptors were prepared all containing two adenine binding sites linked by various spacers.Their ability to act as templates in the coupling of two adenine derivatives, an active ester and an amine, in CHCl3 was evaluated.The accelerations varied from none to 700-fold.Binding studies of the coupling product with these templates confirmed involvement of both binding sites.When the spacer was a 1,10-phenanthroline unit, an efficient hydrolysis reaction of the active ester was observed.Another series of receptors were prepared containing one adenine receptor and various polar functional groups.The molecules were evaluated as catalysts in the coupling of an adenine-derived active ester and n-butylamine.The orientation as well as the nature of the functional group greatly influenced the coupling rate.A carboxylate group was most effective, accelerating the intracomplex reaction 250-fold. - Keywords: adenine * catalysis * molecular recognition * template effects * transition states
- Pieters, Roland J.,Huc, Ivan,Rebek, Julius
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p. 183 - 192
(2007/10/02)
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- Structure-Activity Relationships of N6-Benzyladenosine-5'-uronamides as A3-Selective Adenosine Agonists
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Adenosine analogues modified at the 5'-position as uronamides and/or as N6-benzyl derivatives were synthesized.These derivatives were examined for affinity in radioligand binding assays at the newly discovered rat brain A3 adenosine receptor and at rat brain A1 and A2a receptors. 5'-Uronamide substituents favored A3 selectivity in the order N-methyl > N-ethyl ca. unsubstituted carboxamide > N-cyclopropyl. 5'-(N-Methylcarboxamido)-N6-benzyladenosine was 37-56-fold more selective for A3 receptors.Potency at A3 receptors was enhanced upon substitution of the benzyl substituent with nitro and other groups. 5'-N-Methyluronamides and N6-(3-substitutedbenzyl)adenosines are optimal for potency and selectivity at A3 receptors.A series of 3-(halobenzyl)-5'-N-ethyluronamide derivatives showed the order of potency at A1 and A2a receptors of I ca.Br > Cl > F.At A3 receptors the 3-F derivative was weaker than the other halo derivatives. 5'-N-Methyl-N6-(3-iodobenzyl)adenosine displayed a Ki value of 1.1 nM at A3 receptors and selectivity versus A1 and A2a receptors of 50-fold.A series of methoxybenzyl derivatives showed that a 4-methoxy group best favored A3 selectivity.A 4-sulfobenzyl derivative was a specific ligand at A3 receptors of moderate potency.An aryl amino derivative was prepared as a probe for radioiodination and receptor cross-linking.
- Gallo-Rodriguez, Carola,Ji, Xiao-duo,Melman, Neli,Siegman, Barry D.,Sanders, Lawrence H.,et al.
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p. 636 - 646
(2007/10/02)
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- RUTHENIUM TETRAOXIDE: A MILD REAGENT FOR THE OXIDATION OF 2',3'-O-ISOPROPYLIDENE PURINE NUCLEOSIDES
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2',3'-O-Isopropylidene purine nucleosides have been oxidized with ruthenium tetraoxide to provide the corresponding 5'-carboxylic acids in quantitative yields under neutral conditions.
- Singh, Ambarish K.,Varma, Rajender S.
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p. 2307 - 2310
(2007/10/02)
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- Ruthenium tetraoxide catalyzed oxidation of nucleosides: A facile synthesis of 5'-carboxylic acid derivatives
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Purine and pyrimidine nucleosides have been oxidized to the corresponding 5'-carboxylic acids using potassium persulfate and ruthenium trichloride under basic conditions. The method provides easy access to nucleosides bearing 3'-amino and 5'-carboxylic acid functionalities from 3'-azido compounds as exemplified by oxidation of AZT followed by reduction of the acid.
- Varma,Hogan
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p. 7719 - 7720
(2007/10/02)
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- N6-substituted N-alkyladenosine-5'-uronamides: bifunctional ligands having recognition groups for A1 and A2 adenosine receptors.
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The coronary vasoactivity of N-ethyl-1'-deoxy-1'-(6-amino-9H-purin-9-yl)-beta-D-ribofuranuronamide (NECA, 1) is over 2 orders of magnitude greater than that of adenosine, and the vasoactivity of certain N6-substituted adenosines is as much as 1 order of m
- Olsson,Kusachi,Thompson,Ukena,Padgett,Daly
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p. 1683 - 1689
(2007/10/02)
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