- A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" 18F fluorination of a RGD peptide under ambient aqueous conditions
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A strategy for last-step 18F fluorination of bioconjugated peptides is reported that exploits an "Achilles heel" in the substrate specificity of the fluorinase enzyme. An acetylene functionality at the C-2 position of the adenosine substrate projects from the active site into the solvent. The fluorinase catalyzes a transhalogenation of 5-chlorodeoxy-2- ethynyladenosine (ClDEA) to 5-fluorodeoxy-2-ethynyladenosine (FDEA). Extending a polyethylene glycol linker from the terminus of the acetylene allows the presentation of bioconjugation cargo to the enzyme for 18F labelling. The method uses an aqueous solution (H218O) of [ 18F]fluoride generated by the cyclotron and has the capacity to isotopically label peptides of choice for positron emission tomography (PET).
- Thompson, Stephen,Zhang, Qingzhi,Onega, Mayca,McMahon, Stephen,Fleming, Ian,Ashworth, Sharon,Naismith, James H.,Passchier, Jan,O'Hagan, David
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- Inhibitors of inosine monophosphate dehydrogenase: Probes for antiviral drug discovery
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The role of inosine monophosphate dehydrogenase (IMPDH) at the metabolic branch point of de novo purine nucleotide biosynthesis makes this enzyme an attractive probe for the discovery of antiviral compounds. Introduction of unsaturation at the 2-position of IMP, the natural substrate for IMPDH, produces Michael acceptors at that position, which results in these compounds being inhibitors of IMPDH. Consistent with this mechanism-based molecular design, some of the parent nucleosides exhibited antiviral activity. Copyright Taylor & Francis, Inc.
- Story, Sherry,Gupta, Mukta,Bonsu, Eric,Nair, Vasu
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- Synthesis and evaluation of 2-ethynyl-adenosine-5′-triphosphate as a chemical reporter for protein AMPylation
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Protein AMPylation is a posttranslational modification (PTM) defined as the transfer of an adenosine monophosphate (AMP) from adenosine triphosphate (ATP) to a hydroxyl side-chain of a protein substrate. One recently reported AMPylator enzyme, Vibrio outer protein S (VopS), plays a role in pathogenesis by AMPylation of Rho GTPases, which disrupts crucial signaling pathways, leading to eventual cell death. Given the resurgent interest in this modification, there is a critical need for chemical tools that better facilitate the study of AMPylation and the enzymes responsible for this modification. Herein we report the synthesis of 2-ethynyl-adenosine-5′-triphosphate (2eATP) and its utilization as a non-radioactive chemical reporter for protein AMPylation.
- Creech, Christa,Kanaujia, Mukul,Causey, Corey P.
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- Base-modified GDP-mannose derivatives and their substrate activity towards a yeast mannosyltransferase
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We have previously developed a new class of inhibitors and chemical probes for glycosyltransferases through base-modification of the sugar-nucleotide donor. The key feature of these donor analogues is the presence of an additional substituent at the nucleobase. To date, the application of this general concept has been limited to UDP-sugars and UDP-sugar-dependent glycosyltransferases. Herein, we report for the first time the application of our approach to a GDP-mannose-dependent mannosyltransferase. We have prepared four GDP-mannose derivatives with an additional substituent at either position 6 or 8 of the nucleobase. These donor analogues were recognised as donor substrates by the mannosyltransferase Kre2p from yeast, albeit with significantly lower turnover rates than the natural donor GDP-mannose. The presence of the additional substituent also redirected enzyme activity from glycosyl transfer to donor hydrolysis. Taken together, our results suggest that modification of the donor nucleobase is, in principle, a viable strategy for probe and inhibitor development against GDP-mannose-dependent GTs.
- Collier, Alice,Wagner, Gerd K.
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- Photoinduced Alkylthiolation of Halogenated Purine Nucleosides
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A new highly efficient methodology for the synthesis of biologically important methylmercaptopurine nucleosides is described.The approach represents a substantial improvement over earlier reported methods for this class of compounds.
- Nair, Vasu,Young, David A.
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- Diimidazo[1,2-c:4',5'-e]pyrimidines: Adenosine agonist activity demonstrated by microphysiometry
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Silicon-based microphysiometry, measuring extracellular acidification rate of cells in culture, demonstrated that a series of diimidazo[1,2-c:4',5'-e]pyrimidines were agonists at the human adenosine A1 receptor. 5-amino-7,8-dihydro-3-ribofuranose-8-(R)-(phenyl)-3H-diimidazo[1,2-c:4',5' -e]pyrimidine (2a) had an EC50 of 100 μM and reached 90% of the E(max) produced by R-PIA.
- Camp, David,Green, Jennifer M.,Kaiser, Sonya M.,Moni, Roger W.,Townsend-Nicholson, Andrea,Schofield, Peter R.,Quinn, Ronald J.
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- On the syntheses of 8-heteroaryl-substituted 9-(β-D-ribofuranosyl)-2,6-diaminopurines through Pd-catalyzed coupling in the presence of cupric oxide
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Convenient methods for the preparation of 9-(β-D-ribofuranosyl) derivatives of 8-(2- and 3-thienyl)-2,6-diaminopurine and of 8-(2- and 3-furyl)-2,6-diaminopurine, which are potential antiviral agents has been worked out. The key step was a Pd(0)-catalyzed Stille coupling between 2- and 3-tributylstannylthiophene and 2- and 3-tributylstannylfuran and trimethylsilyl protected 9-(β-D-ribofuranosyl)-2,6-diamino-8-bromopurine. The use of N,N-dimethylformamide as solvent at 110° and dichloro(diphenylphosphine-propane)palladium(II) [PdCl2(dppp)] with cupric oxide as co-reagent was essential in order to obtain a fast reaction and high yields.
- Ozola,Persson,Gronowitz,Hornfeldt
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- Synthesis of complex ethynyladenosines using organic triflic enolates in palladium-atalyzed reactions: Potential agonists for the adenosine A2 receptor
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Many high affinity adenosine A2 receptor agonists contain substituents at position 2 of the purine base. In the search for new methodology to develop C-2 substituted adenosine analogues, we have applied organic triflates in palladium-catalyzed cross-couplings that resulted in new 2-cycloalkylated ethynyl-adenosines. The organic triflates are derived from commercially available ketones and, when used in the crosscouplings, result generally in clean reactions with good yields. These are the first examples of the utilization of organic triflates in palladium-catalyzed cross-coupling reactions in the synthesis of modified nucleosides.
- Adah, Steven A.,Nair, Vasu
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- Facile, chemoenzymatic synthesis of the potent antiviral compound, 2-acetonylinosine
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A facile and efficient methodology for the chemoenzymatic synthesis of the antiviral compound, 2-acetonylinosine has been developed. The present synthetic strategy, which has generality, is a dramatic improvement on the methodologies currently available for the synthesis of functionalized purine nucleosides of therapeutic interest.
- Gupta, Mukta,Nair, Vasu
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- Expedient synthesis of 2-alkylthio-N6-aryladenosines from guanosine
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A general approach for the synthesis of 2-alkylthio-N6-aryladenosine was developed from the commercially available guanosine through the acetyl protection, chlorination, diazotization-alkylthionation, aromatic nucleophilic substitution and deacetylation. Two approaches were designed for the transformation of 2-amino-6-chloroguanosine to 2-alkylthio-N6-aryladenosines but only the one with diazotization-alkylthionation first could afford the target molecules. Both electron-rich and deficient anilines can afford the desired products in moderate to good yield. Finally, under the optimized condition, 20 2-alkylthio-N6-aryladenosines were synthesized, 5 of which exhibit poor antiplatelet aggregation activities.
- Tian, Miao,Chen, Ning,Xu, Fangming,Li, Xiuxiu,Li, Shunlai,Du, Hongguang
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- A facile synthesis of 2-azidoadenosine derivatives from guanosine as photoaffinity probes
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2-Azidoadenosine (1) was synthesized in an overall yield of 49% from guanosine via the reaction of 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloropurine (2) with isoamyl nitrite and trimethylsilyl azide under neutral and anhydrous conditions. As photoaffinity probes, ATP analogues and the cap structure of eukaryotic mRNA bearing 2-azidoadenosine were synthesized.
- Higashiya, Seiichiro,Kaibara, Chitose,Fukuoka, Koichiro,Suda, Fuminori,Ishikawa, Masahide,Yoshida, Masasuke,Hata, Tsujiaki
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- Modular, Step-Efficient Palladium-Catalyzed Cross-Coupling Strategy to Access C6-Heteroaryl 2-Aminopurine Ribonucleosides
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Two Pd-catalyzed methods to access 6-heteroaryl 2-aminopurine ribonucleosides from 6-chloroguanosine are described. First, Pd-132-catalyzed Suzuki-Miyaura cross-coupling using a series of boron substrates and 6-chloroguanosine forms 6-heteroaryl-2-aminopurines in a single step. The versatility of 6-chloroguanosine is further demonstrated using a modified Sonogashira coupling employing potassium iodide as an additive. Finally, the utility of the 6-alkynyl-2-aminopurine ribonucleoside as a dipolarophile in [3 + 2] cycloadditions is presented, affording triazoles and isoxazoles when reacted with azide and isonitrile 1,3-dipoles, respectively.
- Buchanan, Helena S.,Pauff, Steven M.,Kosmidis, Tilemachos D.,Taladriz-Sender, Andrea,Rutherford, Olivia I.,Hatit, Marine Z. C.,Fenner, Sabine,Watson, Allan J. B.,Burley, Glenn A.
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- Efficient methods for the synthesis of [2-15N]guanosine and 2′-deoxy[2-15N]guanosine derivatives
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The nucleophilic addition-elimination reaction of 2′,3′, 5′-tri-O-acetyl-2-fluoro-O6-[2-(4-nitrophenyl)ethyl]inosine (8) with [15N]benzylamine in the presence of triethylamine afforded the N2-benzyl[2-15N]guanosine derivative (13) in a high yield, which was further convened into the N2-benzoyl[2-15N] guanosine derivative by treatment with ruthenium trichloride and tetrabutylammonium periodate. A similar sequence of reactions of 2′, 3′, 5′-tri-O-acetyl-2-fluoro-O6-[2-(methylthio)ethyl]inosine (9) and the 6-chloro-2-fluoro-9-(β-D-ribofuranosyl)-9H-purine derivative (11), which were respectively prepared from guanosine, with potassium [15N]phthalimide afforded the N2-phthaloyl [2-15N]guanosine derivative (15; 62%) and 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2- [15N]phthalimido-9H-purine (17; 64%), respectively. Compounds 15 and 17 were then efficiently converted into 2′,3′,5′-tri-O-acetyl [2-15N]guanosine. The corresponding 2′-deoxy derivatives (16 and 18) were also synthesized through similar procedures.
- Kamaike,Kinoshita,Niwa,Hirose,Suzuki,Ishido
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- 2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5′-nucleotidase (CD73) Inhibitors with Variable Binding Modes
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CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.
- Bhattarai, Sanjay,Pippel, Jan,Scaletti, Emma,Idris, Riham,Freundlieb, Marianne,Rolshoven, Georg,Renn, Christian,Lee, Sang-Yong,Abdelrahman, Aliaa,Zimmermann, Herbert,El-Tayeb, Ali,Müller, Christa E.,Str?ter, Norbert
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supporting information
p. 2941 - 2957
(2020/04/10)
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- Synthesis and biological evaluation of a novel C8-pyrrolobenzodiazepine (PBD) adenosine conjugate. A study on the role of the PBD ring in the biological activity of PBD-conjugates
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Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD-ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to affect and modulate the biological and biophysical properties of PBD hybrids.
- Bhakta, Sanjib,Brucoli, Federico,Ferguson, Lindsay,Fox, Keith R.,Wells, Geoff
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supporting information
(2020/03/19)
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- Essential Structural Profile of Novel Adenosine Derivatives as Antiplatelet Aggregation Inhibitors Based on 3D-QSAR Analysis Using CoMFA, CoMSIA, and SOMFA
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Abstact: —In this study, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and the self-organizing molecular field analysis (SOMFA) were performed on a series of novel adenosine derivatives. Significant correlation coefficients (CoMFA, q2 = 0.560, r2 = 0.940, F value = 71.850, and SEE = 0.097; CoMSIA, q2 = 0.528, r2 = 0.943, F value = 29.29 and SEE = 0.108; SOMFA, r2 = 0.615, r2cr= 0.577, F value = 60.797, and SEE = 0.226) were obtained, and the generated models were validated using test sets. By analyzing the corresponding contour maps in detail, new adenosine derivatives with potential efficacy were designed for synthesis in the future.
- Bao, XueFeng,Du, Hongguang,Liu, Guocheng,Lu, Chenghu,Ren, Chaorui,Shunlai, Li
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p. 448 - 457
(2020/06/30)
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- Chemical Synthesis of Oligoribonucleotide (ASL of tRNALys T. brucei) Containing a Recently Discovered Cyclic Form of 2-Methylthio-N6-threonylcarbamoyladenosine (ms2ct6A)
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The synthesis of the protected form of 2-methylthio-N6-threonylcarbamoyl adenosine (ms2t6A) was developed starting from adenosine or guanosine by using the optimized carbamate method and, for the first time, an isocyanate route. The hypermodified nucleoside was subsequently transformed into the protected ms2t6A-phosphoramidite monomer and used in a large-scale synthesis of the precursor 17nt ms2t6A-oligonucleotide (the anticodon stem and loop fragment of tRNALys from T. brucei). Finally, stereochemically secure ms2t6A→ms2ct6A cyclization at the oligonucleotide level efficiently afforded a tRNA fragment bearing the ms2ct6A unit. The applied post-synthetic approach provides two sequentially homologous ms2t6A- and ms2ct6A-oligonucleotides that are suitable for further comparative structure–activity relationship studies.
- Debiec, Katarzyna,Matuszewski, Michal,Podskoczyj, Karolina,Leszczynska, Grazyna,Sochacka, Elzbieta
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supporting information
(2019/08/26)
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- S-Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C-Alkylation
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A tandem enzymatic strategy to enhance the scope of C-alkylation of small molecules via the in situ formation of S-adenosyl methionine (SAM) cofactor analogues is described. A solvent-exposed channel present in the SAM-forming enzyme SalL tolerates 5′-chloro-5′-deoxyadenosine (ClDA) analogues modified at the 2-position of the adenine nucleobase. Coupling SalL-catalyzed cofactor production with C-(m)ethyl transfer to coumarin substrates catalyzed by the methyltransferase (MTase) NovO forms C-(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications. Establishing the molecular determinants that influence C-alkylation provides the basis to develop a late-stage enzymatic platform for the preparation of high value small molecules.
- McKean, Iain J. W.,Sadler, Joanna C.,Cuetos, Anibal,Frese, Amina,Humphreys, Luke D.,Grogan, Gideon,Hoskisson, Paul A.,Burley, Glenn A.
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supporting information
p. 17583 - 17588
(2019/11/11)
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- Synthesis, characterization and biological evaluation of purine nucleoside analogues
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We present a convenient route for the synthesis of C6-amino-C5′-N-cyclopropyl carboxamido-C2-alkynylated purine nucleoside analogues 11a–g via Sonogashira coupling reaction. The nine step synthesis is easy to perform, employing commercially available reagents. Compound 9 is used as key intermediate for the synthesis of analogues 11a–g. Synthetic intermediates and final products are appropriately characterized by IR, 1H NMR, 13C NMR and Mass. The modified nucleoside analogues 11a–g is evaluated for in vitro anticancer activity against MDA-MB-231 and Caco-2 cell lines. Screening data reveals that compounds 11b and 11e displayed potent IC50 value of 7.9, 6.8 μg/mL respectively against MDA-MB-231 and of 7.5, 8.3 μg/mL respectively against Caco-2 than the standard drug doxorubicin, thus establishing the potential anti-cancer properties of these newer derivatives.
- Malthum, Shankaraiah,Polkam, Naveen,Allaka, Tejeswara Rao,Chepuri, Kalyani,Anireddy, Jaya Shree
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supporting information
p. 4166 - 4168
(2017/10/13)
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- A New Class of Fluorinated A2A Adenosine Receptor Agonist with Application to Last-Step Enzymatic [18F]Fluorination for PET Imaging
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The A2A adenosine receptor belongs to a family of G-coupled protein receptors that have been subjected to extensive investigation over the last few decades. Due to their prominent role in the biological functions of the heart, lungs, CNS and brain, they have become a target for the treatment of illnesses ranging from cancer immunotherapy to Parkinson's disease. The imaging of such receptors by using positron emission tomography (PET) has also been of interest, potentially providing a valuable tool for analysing and diagnosing various myocardial and neurodegenerative disorders, as well as offering support to drug discovery trials. Reported herein are the design, synthesis and evaluation of two new 5′-fluorodeoxy-adenosine (FDA)-based receptor agonists (FDA-PP1 and FDA-PP2), each substituted at the C-2 position with a terminally functionalised ethynyl unit. The structures enable a synthesis of 18F-labelled analogues by direct, last-step radiosynthesis from chlorinated precursors using the fluorinase enzyme (5′-fluoro-5′-deoxyadenosine synthase), which catalyses a transhalogenation reaction. This delivers a new class of A2A adenosine receptor agonist that can be directly radiolabelled for exploration in PET studies.
- Lowe, Phillip T.,Dall'Angelo, Sergio,Mulder-Krieger, Thea,IJzerman, Adriaan P.,Zanda, Matteo,O'Hagan, David
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p. 2156 - 2164
(2017/10/07)
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- Synthesis, characterization and biological evaluation of C5′-N-cyclopropylcarboxamido-C6-amino-C2-alkynylated purine nucleoside analogues
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In an effort to develop potent antibacterial and anticancer agents, a series of C5′-N-cyclopropylcarboxamido-C6-amino-C2-alkynylated purine nucleoside analogues 11a-g were synthesized through a Sonogashira cross-coupling reaction. The nine-step synthesis is easy to perform, and employs commercially available reagents. 2-Iodo-5′-N-cyclopropylcarboxamidoadenosine (9) was used as the starting intermediate for the synthesis of title derivatives 11a-g. Synthetic intermediates (2–9) and final products (11a-g) were appropriately characterized by IR, 1H NMR, 13C NMR and mass spectroscopy. The synthesized purine nucleoside analogues (11a-g) were evaluated for their in vitro antibacterial activity against two gram-positive and two gram-negative bacteria. They were then tested for cytotoxicity against MDA-MB-231 and Caco-2 cancer cell lines to determine their anti-cancer activity. Among the tested compounds, compounds 11c and 11g showed most potent antibacterial activity against S.aureus and P.aeruginosa bacterial strains. Compounds 11b and 11e displayed considerable IC50s of 7.9 and 6.8 μg/mL, respectively, vs MDA-MB-231 cell lines of 7.5 and 8.3 μg/mL, respectively, against the Caco-2 cell lines.
- Ananda Mohan, Arasavelli,Veera Raghava Sharma, Ganapavarapu,Vidavalur, Siddaiah
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p. 637 - 651
(2017/12/06)
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- Kengreal intermediates as well as preparation methods and application thereof
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The invention discloses Kengreal intermediates as well as preparation methods and an application thereof. The intermediates respectively comprise chemical structures as shown in formula VI and formula VII. The intermediates can be applied to synthesis of a known key intermediate TEPAD of Kengreal, and the method has advantages of high total molar yield, simple operation without special requirements for equipment, safety without pollution, low cost, and the like; the method has extremely high practical value for industrialization of Kengreal, and compared with the prior art, the method has significant progress.
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- Effective synthesis of nucleosides utilizing O-acetyl-glycosyl chlorides as glycosyl donors in the absence of catalyst: Mechanism revision and application to silyl-hilbert-johnson reaction
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An effective synthesis of nucleosides using glycosyl chlorides as glycosyl donors in the absence of Lewis acid has been developed. Glycosyl chlorides have been shown to be pivotal intermediates in the classical silyl-Hilbert-Johnson reaction. A possible mechanism that differs from the currently accepted mechanism advanced by Vorbrueggen has been proposed and verified by experiments. In practice, this catalyst-free method provides easy access to Capecitabine in high yield.
- Liang, Chengyuan,Ju, Weihui,Ding, Shunjun,Sun, Han,Mao, Gennian
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- Synthesis of 8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides with a straightforward multiple-functionalization strategy
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A straight forward strategy to synthesize purine nucleosides with multiple functionalization on 2-, 6-, and 8-positions has been developed successfully, which provides a series of 8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides in moderate to good yields for further biological and medical activity screening.
- Du, Hongguang,Sun, Xiaoyang,Yu, Mingwu,Tian, Miao,Li, Shunlai,Wang, Zhiqian
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supporting information
p. 2949 - 2953
(2016/07/06)
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- Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors
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Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that 18 may offer a novel treatment option for human colorectal cancer.
- Yoon, Suyoung,Kim, Jong Hyun,Kim, Sung-Eun,Kim, Changhoon,Tran, Phuong-Thao,Ann, Jihyae,Koh, Yura,Jang, Jayun,Kim, Sungmin,Moon, Hee-Sun,Kim, Won Kyung,Lee, Sangkook,Lee, Jiyoun,Kim, Sunghoon,Lee, Jeewoo
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p. 10322 - 10328
(2016/12/07)
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- 2-catalyzed directed N -Boc amidation of arenes "on water"
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Rhodium(III) catalysis "on water" is effective for directed C-H amidation of arenes. The catalytic process is promoted by OH groups present on the hydrophobic water surface and is inefficient in all (most) common organic solvents investigated so far. In the presence of easily prepared tert-butyl 2,4-dinitrophenoxycarbamate, a new and stable nitrene source, the "on water" reaction can efficiently provide the desired N-Boc-aminated products with good functional group tolerance.
- Ali, Md Ashif,Yao, Xiayin,Sun, Hao,Lu, Hongjian
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supporting information
p. 1513 - 1516
(2015/03/30)
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- Ribofuranosyl Purine Compounds, Methods for Preparing the Same and Use Thereof
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The present invention relates to the compounds of the formulae (I) and (I-1) and the process for preparing the same, uses of the compounds for the treatment of diseases associated with platelet aggregation and in the manufacture of a medicament for the treatment of diseases associated with platelet aggregation, and relates to a pharmaceutical composition and a pharmaceutical formulation containing the compounds, wherein the definitions of R1, R2, R3 and R2a in the formulae are the same as those in the description.
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Paragraph 0067; 0068
(2014/02/15)
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- Synthesis and structure-activity relationships of 2-hydrazinyladenosine derivatives as A2A adenosine receptor ligands
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A series of 2-hydrazinyladenosine derivatives was synthesized and investigated in radioligand binding studies for their affinity at the adenosine receptor subtypes with the goal to obtain potent and A2AAR selective agonists and to explore the structure-activity relationships of this class of compounds at A2AAR. Modifications included introduction of a second sugar moiety at position 2 of adenosine to form new bis-sugar nucleosides and/or modifications of the 2-position linker in different ways. The performed modifications were found to produce compounds with relatively high A 2AAR affinity and very high selectivity toward A2AAR. The most potent bis-sugar nucleoside was obtained with the D-galactose derivative 16 which exhibited a Ki value of 329 nM at A2AAR with marked selectivity against the other AR subtypes. In another set of compounds, compound 3 was modified via replacement of its cyclic structure with mono- and disubstituted phenyl moieties and the resulting hydrazones 10-14 were found to have low nanomolar affinity for A2AAR. In addition to 3, compounds 10, 11 and 13 have been identified as the most potent compounds in the present series with Ki values of 16.1, 24.4, and 12.0 nM, respectively, at rat A2AAR. Species differences were tested and found to exist in different rates. Functional properties of the most potent compounds 10, 11, 13 and 16 were assessed showing that the compounds acted as agonists at A 2AAR.
- El-Tayeb, Ali,Gollos, Sabrina
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supporting information
p. 436 - 447
(2013/03/14)
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- RIBOFURANOSYL PURINE COMPOUND, PREPARATION METHOD THEREFOR, AND USE THEREOF
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The present invention relates to the compounds of the formulae (I) and (I-1) and the process for preparing the same, uses of the compounds for the treatment of diseases associated with platelet aggregation and in the manufacture of a medicament for the treatment of diseases associated with platelet aggregation, and relates to a pharmaceutical composition and a pharmaceutical formulation containing the compounds, wherein the definitions of R1, R2, R3 and R2a in the formulae are the same as those in the description.
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Paragraph 0050
(2014/01/07)
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- Synthesis and anti-HIV activity of a series of 6-modified 2′,3′-dideoxyguanosine and 2′,3′-didehydro-2′, 3′-dideoxyguanosine analogs
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In search of potential 2′,3′-dideoxyguanosine (ddG) and 2′,3′-didehydro-2′,3′-dideoxyguanosine (D4G) prodrugs, a series of 6-modified ddG, D4G analogs were synthesized and evaluated for their anti-HIV activities and cytotoxities in cell-based assays. All analogs showed low cytotoxicities and some of them displayed benign anti-HIV activities. The active triphosphate forms in vivo, ddGTP and D4TTP, were also synthesized by a novel and facile one-pot method. The recognition of ddGTP and D4TTP by Taq, Therminater DNA polymerase and HIV reverse transcriptase (RT) incorporated in DNA/RNA strands were investigated by a non-radioactivity method and K m were determined. A series of 6-modified 2′,3′- dideoxyguanosine and 2′,3′-didehydro-2′,3′- dideoxyguanosine analogs were synthesized. Anti-HIV activity was investigated in cell-based assay. ddGTP was synthesized as well as D4TTP by a novel one-pot method, and the incorporation efficiencies recognized by DNA polymerase and HIV reverse transcriptase (HIV RT) were evaluated. Copyright
- Xie, Lujia,Yang, Xiantao,Pan, Delin,Cao, Yingli,Cao, Mou,Lin, Guichun,Guan, Zhu,Guo, Ying,Zhang, Lihe,Yang, Zhenjun
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p. 1207 - 1218
(2013/10/21)
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- Synthesis of N6-alkyl(aryl)-2-alkyl(aryl)thioadenosines as antiplatelet agents
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A series of novel N6-alkyl(aryl)-2-alkyl(aryl)thioadenosines were synthesized, and their human antiplatelet aggregation activities were evaluated by the stimulation of adenosine 5′-diphosphate (ADP). Some of these compounds showed strong activity, among which compound 5b11 displayed the highest activity with an IC50 value of 29 ± 3 μM. Furthermore, five compounds were tested against arachidonic acid (AA)-induced human platelet aggregation. The results showed that compound 5b10 exhibited the highest activity with an IC50 value of 3 ± 2 μM. The adenosine derivatives substituted with a phenethyl group at the N6 position and a methylthio or ethylthio group at the C-2 position displayed high antiplatelet aggregation activity.
- Liu, Guocheng,Xu, Jiaxi,Chen, Ning,Zhang, Si,Ding, Zhongren,Du, Hongguang
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supporting information; experimental part
p. 114 - 123
(2012/08/28)
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- Evidence for the existence of a specific gprotein-coupled receptor activated by guanosine
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Guanosine, released extracellularly from neurons and glial cells, plays important roles in the central nervous system, including neuroprotection. The innovative DELFIA Eu-GTP binding assay was optimized for characterization of the putative guanosine receptor binding site at rat brain membranes by using a series of novel and known guanosine derivatives. These nucleosides were prepared by modifying the purine and sugar moieties of guanosine at the 6- and 5'-positions, respectively. Results of these experiments prove that guanosine, 6-thioguanosine, and their derivatives activate a Gprotein-coupled receptor that is different from the well-characterized adenosine receptors. Catching the elusive guanosine receptor: The innovative DELFIA Eu-GTP binding assay was applied to characterize the guanosine binding site by using novel and known guanosine derivatives. Some of the tested compounds, which proved to be full agonists with EC50 values in the low nanomolar range, could be useful tools for further characterization of the putative guanosine receptor.
- Volpini, Rosaria,Marucci, Gabriella,Buccioni, Michela,DalBen, Diego,Lambertucci, Catia,Lammi, Carmen,Mishra, Ram C.,Thomas, Ajiroghene,Cristalli, Gloria
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scheme or table
p. 1074 - 1080
(2012/01/06)
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- RNA as scaffold for pyrene excited complexes
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Synthesis and spectral properties of 1-ethynylpyrene base modified RNA are reported. The fluorophore attached to the 2-position of adenosine is directed into the easily accessible minor groove in RNA. Through an intermolecular interaction of the pyrene residues in twofold labelled RNA, single and double strands can be distinguished by their fluorescence maxima around 450 and 480 nm, respectively. This behaviour allows the kinetic investigation of RNA hybridisation and folding by fluorescence spectroscopy.
- Gruenewald, Christian,Kwon, Taewoo,Piton, Nelly,Foerster, Ute,Wachtveitl, Josef,Engels, Joachim W.
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- Synthesis of novel C6-phosphonated purine nucleosides under microwave irradiation by SNAr-arbuzov reaction
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(Chemical Equation Presented) Novel C6-phosphonated purine nucleosides were obtained in good to excellent isolated yields by the simple and catalyst-free SNAr-Arbuzov reaction of trialkyl phosphite with 6-choloropurine nucleosides, including a series of n
- Qu, Gui-Rong,Xia, Ran,Yang, Xi-Ning,Li, Jian-Guo,Wang, Dong-Chao,Guo, Hai-Ming
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p. 2416 - 2419
(2008/09/18)
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- A1 adenosine receptor agonists
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Disclosed are novel compounds that are A1 adenosine receptor agonists, useful for treating various disease states, in particular tachycardia and atrial flutter, angina, diseases related to release of nonesterified fatty acids, and myocardial in
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Page/Page column 6; 9-10
(2008/06/13)
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- INDUCTION OF PHARMACOLOGICAL STRESS WITH ADENOSINE RECEPTOR AGONISTS
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A method is provided employing A2A adenosine receptor agonists as vasodilators to detect the presence and assess the severity of coronary artery stenosis.
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Page/Page column 9
(2010/02/10)
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- 2-(N-Acyl) and 2-N-acyl-N6-substituted analogues of adenosine and their affinity at the human adenosine receptors
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A series of 2-(N-acyl) and 2-(N-acyl)-N6-alkyladenosine analogues have been synthesized from the intermediate 2-amino-6-chloroadenosine derivatives (2b and 7) and evaluated for their affinity at the human A 1, A2A, and A3 receptors. We found that 2-(N-acyl) derivatives of adenosine showed relatively low affinity at A 2A and A3 receptors, while the N6-cyclopentyl substituent in 4h and 4i induced high potency [A1 (K i)=20.7 and 31.8 nM respectively] at the A1 receptor and resulted therefore in increased selectivity for this subtype. The general synthetic methods and their binding studies are presented herein.
- Jagtap, Prakash G.,Chen, Zhiyu,Szabo, Csaba,Klotz, Karl-Norbert
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p. 1495 - 1498
(2007/10/03)
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- ADENOSINE A3 RECEPTOR AGONISTS
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Disclosed are novel adenosine A3 receptor agonists, useful for treating various disease states, including neurological and cardiac ischemia, asthma, leukopenia and neutropenia, cancer and inflammation.
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Page 13; 23-24
(2008/06/13)
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- Modulation of adenosine receptor affinity and intrinsic efficacy in adenine nucleosides substituted at the 2-position
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We studied the structural determinants of binding affinity and efficacy of adenosine receptor (AR) agonists. Substituents at the 2-position of adenosine were combined with N6-substitutions known to enhance human A 3AR affinity. Selectivity of binding of the analogues and their functional effects on cAMP production were studied using recombinant human A1, A2A, A2B, and A3ARs. Mainly sterically small substituents at the 2-position modulated both the affinity and intrinsic efficacy at all subtypes. The 2-cyano group decreased hA3AR affinity and efficacy in the cases of N6-(3-iodobenzyl) and N 6-(trans-2-phenyl-1-cyclopropyl), for which a full A3AR agonist was converted into a selective antagonist; the 2-cyano-N 6-methyl analogue was a full A3AR agonist. The combination of N6-benzyl and various 2-substitutions (chloro, trifluoromethyl, and cyano) resulted in reduced efficacy at the A1AR. The environment surrounding the 2-position within the putative A3AR binding site was explored using rhodopsin-based homology modeling and ligand docking.
- Ohno, Michihiro,Gao, Zhan-Guo,Van Rompaey, Philippe,Tchilibon, Susanna,Kim, Soo-Kyung,Harris, Brian A.,Gross, Ariel S.,Duong, Heng T.,Van Calenbergh, Serge,Jacobson, Kenneth A.
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p. 2995 - 3007
(2007/10/03)
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- Synthesis of 2-aralkoxyadenosines and 2-alkoxyadenosines
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The invention provides new methods for synthesis of 2-aralkyloxyadenosines and 2-alkoxyadenosines. The invention is particularly useful for synthesis of 2-[2-(4-chlorophenyl)ethoxy]adenosine. Preferred methods of the invention include activating a guanosine compound followed by hydrolysis; alkylating the hydrolyzed compound with subsequent animation to provide a 2-aralkyloxyadenosine or a 2-alkoxyadenosine compound.
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Page/Page column 4
(2008/06/13)
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- Reaction of arylnitrenium ions with guanine derivatives: N1-methylguanosine and N2,N2-dimethylguanosine
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A prior flash photolysis study of the direct reaction of arylnitrenium ions with 2′-deoxyguanosine identified a second intermediate that grew in as the transient nitrenium ion reacted with the nucleoside. This intermediate was identified as the the product of the addition of the nitrenium ion to the C-8 position of guanine prior to loss of the C-8 proton - the C-8 intermediate. A feature of the C-8 intermediate is that it exists in acid-base forms. This behavior was evident in both a spectroscopic analysis as well as in the rate-pH profile, which showed a break around pH 4 from a pH-independent reaction to a reaction that was first-order in H+. The present study was designed to identify the structure of the conjugate base form. This involved a kinetic study of the decay of the C-8 intermediate derived from the reaction of the 2-fluorenylnitrenium ion with N1-methylguanosine and N2,N2-dimethylguanosine. The rationale was that the former is unable to lose the N-1 proton, while the latter cannot deprotonate at the NH2 group. The rate-pH profiles clearly show that it is the N-1 proton that is acidic. The rate constants for the C-8 intermediate of N2,N2-dimethylguanosine show the same downward break observed with 2′-deoxyguanosine and guanosine associated with conversion to the conjugate base form. In contrast, the rate constants for the N1-methylguanosine intermediate are independent of pH. Rate constants for the reaction forming the C-8 intermediate are also reported. These show that the reaction of nitrenium ions with the N2,N2-dimethylguanine derivative is significantly faster (except where the reactions are diffusion controlled). This is consistent with the initial step of the reaction of an arylnitrenium ion and guanine occurring by direct addition at C-8. The developing positive charge in such a reaction can be delocalized to the C-2 position where π donors such as NH2 and NMe2 can exert a stabilizing effect.
- Cheng, Bernice,McClelland, Robert A.
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p. 1881 - 1886
(2007/10/03)
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- Methods and compositions for treating inflammatory response
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Compounds and methods are provided to treat inflammatory conditions with certain A2Aadenosine receptor antagonists.
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- The discovery and synthesis of highly potent, A(2a) receptor agonists
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A series of N6,2-disubstituted adenosine analogues have been synthesized and their functional activity measured against A(2a) and A1 receptors. Examples of compounds with both a lipophilic N6-substituent and amino-functionalized 2-position were highly active at the A(2a) receptor on the human neutrophil. (C) 2000 Published by Elsevier Science Ltd. All rights reserved.
- Keeling, Suzanne E.,Albinson, F. David,Ayres, Barry E.,Butchers, Peter R.,Chambers, C. Lynn,Cherry, Peter C.,Ellis, Frank,Ewan, George B.,Gregson, Michael,Knight, John,Mills, Keith,Ravenscroft, Paul,Reynolds, Linda H.,Sanjar, Shahin,Sheehan, Michael J.
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p. 403 - 406
(2007/10/03)
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- Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: Elucidation of a novel binding mode for a 2-Amino-N6-substituted adenosine
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As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N6-, 2-amino-N6-, and N2-substituted adenosine analogues were synthesized and tested to establish structure - activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for N6-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N6-[2-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 μM. 2-[[2-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 μM. To explore the potential of an additive effect that having the N6 and N2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N6,N2-disubstituted adenosine analogues to yield N6-(2-phenylethyl)-2-[(2-phenylethyl)amino]adenosine (69) as a 30 μM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 A? X-ray structure of a T. brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this 'flipped and rotated' binding mode.
- Bressi,Choe,HoughHough,Buckner,Van Voorhis,Verlinde,Hol,Gelb
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p. 4135 - 4150
(2007/10/03)
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- New base-altered adenosine analogues: Synthesis and affinity at adenosine A1 and A(2A) receptors
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N6-Substituted adenosine analogues containing cyclic hydrazines or chiral hydroxy (ar)alkyl groups, designed to interact with the S2 and S3 receptor subregions, have been synthesized and their binding to the adenosine A1 and A(2A) receptors have been investigated. Examples of both types of compounds were found to exhibit highly selective binding (K(i) in low nM range) to the rat A1 receptor.
- Ha, Seung B.,Melman, Neli,Jacobson, Kenneth A.,Nair, Vasu
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p. 3085 - 3090
(2007/10/03)
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- Synthesis of high specific activity tritium labelled [2-3H]-adenosine-5'-triphosphates
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A procedure for high level tritium labelling at the C2-H position of adenosine 5'-triphosphate ([2-3H]-ATP, 1), based on the tritiodehalogenation reaction of 2-bromoadenosine 5'-triphosphate (2) has been elaborated. This precursor was prepared in a six-step synthesis from guanosine. The tritiodehalogenation of (2) for three hours over palladium oxide in phosphate buffer yielded tritium labelled ATP with high specific activity, in good chemical yield.
- De Jaiswal, Vendra K.,Morimoto, Hiromi,Trump, Eric L.,Williams, Philip G.,Wemmer, David E.
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p. 743 - 752
(2007/10/03)
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- Conversion of guanosine into acyclovir and its 6-deoxy derivative
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2-amino-6-(4-chlorophenylthio)-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl) purine 11, which is readily prepared by allowing the corresponding 6-chloro-compound 10 to react with 4-chloro(thiophenol) and triethylamine in methanol solution at room temperature, reacts with boron trifluoride diethyl etherate in boiling dichloromethane solution to give 2-amino-6-(4-chlorophenylthio)-9H-purine 12 in high isolated yield. 9-[(2-acetoxyethoxy)methyl]-2-amino-6-(4-chlorophenylthio)-9H-purine 13, prepared from the latter aglycone 12 in good yield, is converted by a four-step process into acyclovir 1 and by a two-step process into 6-deoxyacyclovir 2.
- Buck, Ildiko M.,Eleuteri, Alessandra,Reese, Colin B.
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p. 9195 - 9206
(2007/10/02)
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- Characterization of cladribine and its related compounds by high- performance liquid chromatography/mass spectrometry
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High-performance liquid chromatography/mass spectrometer (HPLC/MS) was used to identify and structurally characterize the modified nucleoside cladribine (2-chloro-2'-deoxy-β-adenosine) and 13 synthesis-related byproducts in bulk drug. Confirmation of compound identity was accomplished by spectral analysis (1H and 13C NMR spectroscopy, mass spectrometry, and UV absorption spectroscopy) of the related compounds as isolated from crude mixtures of the drug substance and by spiking experiments with authentic standards. The use of on-line mass spectrometric analysis (i.e., LC/MS) to augment UV absorption spectra permitted rapid identification of many of the compounds of interest.
- Weber,Sampino,Dunphy,Burinsky,Williams,Motto
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p. 525 - 531
(2007/10/02)
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