- Structure-Guided Tuning of a Selectivity Switch towards Ribonucleosides in Trypanosoma brucei Purine Nucleoside 2′-Deoxyribosyltransferase
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The use of nucleoside 2′-deoxyribosyltransferases (NDTs) as biocatalysts for the industrial synthesis of nucleoside analogues is often hindered by their strict preference for 2′-deoxyribonucleosides. It is shown herein that a highly versatile purine NDT from Trypanosoma brucei (TbPDT) can also accept ribonucleosides as substrates; this is most likely because of the distinct role played by Asn53 at a position that is usually occupied by Asp in other NDTs. Moreover, this unusual activity was improved about threefold by introducing a single amino acid replacement at position 5, following a structure-guided approach. Biophysical and biochemical characterization revealed that the TbPDTY5F variant is a homodimer that displays maximum activity at 50 °C and pH 6.5 and shows a remarkably high melting temperature of 69 °C. Substrate specificity studies demonstrate that 6-oxopurine ribonucleosides are the best donors (inosine>guanosine?adenosine), whereas no significant preferences exist between 6-aminopurines and 6-oxopurines as base acceptors. In contrast, no transferase activity could be detected on xanthine and 7-deazapurines. TbPDTY5F was successfully employed in the synthesis of a wide range of modified ribonucleosides containing different purine analogues.
- Del Arco, Jon,Mills, Alberto,Gago, Federico,Fernández-Lucas, Jesús
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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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- Protonation studies of modified adenine and adenine nucleotides by theoretical calculations and 15N NMR
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The acid/base character of nucleobases affects phenomena such as self-association, interaction with metal ions, molecular recognition by proteins, and nucleic acid base-pairing. Therefore, the investigation of proton-transfer equilibria of natural and synthetic nucleos(t)ides is of great importance to obtain a deeper understanding of these phenomena. For this purpose, a set of ATP prototypes was investigated using 15N NMR spectroscopy, and the corresponding adenine bases were investigated by theoretical calculations. 15N NMR measurements provided not only acidity constants but also information on the protonation site(s) on the adenine ring and regarding the ratio of the singly protonated species in equilibrium. Substituents of different nature and position on the adenine ring did not change the preferred protonation site, which remained N1. However, for 2-thioether-ATP derivatives a mixed population of N1 and N7 singly protonated species was observed. Reduction of basicity of 0.4-1 pKa units relative to ATP was also observed for all evaluated ATP derivatives, except for 2-Cl-ATP, for which Ka was ca. 10,000-fold lower. To explain the substitution-dependent variations in the experimental pKa values of the ATP analogues, gas-phase proton affinities (PA), ΔΔGhyd, and pKa values of the corresponding adenine bases were calculated using quantum mechanical methods. The computed PA and ΔΔGhyd values successfully explained the experimental pKa values. A computational procedure for the prediction of accurate pKa values was developed using density functional theory and polarizable continuum model calculations. In this procedure, we developed a set of parameters for the polarizable continuum model that was fitted to reproduce experimental pKa values of nitrogen heterocycles. This method is proposed for the prediction of pKa values and protonation site(s) of purine analogues that have not been synthesized or analyzed.
- Major, Dan T.,Laxer, Avital,Fischer, Bilha
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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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p. 2941 - 2957
(2020/04/10)
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- Thermodynamic Reaction Control of Nucleoside Phosphorolysis
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Nucleoside analogs represent a class of important drugs for cancer and antiviral treatments. Nucleoside phosphorylases (NPases) catalyze the phosphorolysis of nucleosides and are widely employed for the synthesis of pentose-1-phosphates and nucleoside analogs, which are difficult to access via conventional synthetic methods. However, for the vast majority of nucleosides, it has been observed that either no or incomplete conversion of the starting materials is achieved in NPase-catalyzed reactions. For some substrates, it has been shown that these reactions are reversible equilibrium reactions that adhere to the law of mass action. In this contribution, we broadly demonstrate that nucleoside phosphorolysis is a thermodynamically controlled endothermic reaction that proceeds to a reaction equilibrium dictated by the substrate-specific equilibrium constant of phosphorolysis, irrespective of the type or amount of NPase used, as shown by several examples. Furthermore, we explored the temperature-dependency of nucleoside phosphorolysis equilibrium states and provide the apparent transformed reaction enthalpy and apparent transformed reaction entropy for 24 nucleosides, confirming that these conversions are thermodynamically controlled endothermic reactions. This data allows calculation of the Gibbs free energy and, consequently, the equilibrium constant of phosphorolysis at any given reaction temperature. Overall, our investigations revealed that pyrimidine nucleosides are generally more susceptible to phosphorolysis than purine nucleosides. The data disclosed in this work allow the accurate prediction of phosphorolysis or transglycosylation yields for a range of pyrimidine and purine nucleosides and thus serve to empower further research in the field of nucleoside biocatalysis. (Figure presented.).
- Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
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p. 867 - 876
(2020/01/24)
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- General Principles for Yield Optimization of Nucleoside Phosphorylase-Catalyzed Transglycosylations
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The biocatalytic synthesis of natural and modified nucleosides with nucleoside phosphorylases offers the protecting-group-free direct glycosylation of free nucleobases in transglycosylation reactions. This contribution presents guiding principles for nucleoside phosphorylase-mediated transglycosylations alongside mathematical tools for straightforward yield optimization. We illustrate how product yields in these reactions can easily be estimated and optimized using the equilibrium constants of phosphorolysis of the nucleosides involved. Furthermore, the varying negative effects of phosphate on transglycosylation yields are demonstrated theoretically and experimentally with several examples. Practical considerations for these reactions from a synthetic perspective are presented, as well as freely available tools that serve to facilitate a reliable choice of reaction conditions to achieve maximum product yields in nucleoside transglycosylation reactions.
- Kaspar, Felix,Giessmann, Robert T.,Hellendahl, Katja F.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
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p. 1428 - 1432
(2020/02/05)
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- Design, synthesis and biological evaluation of 2-hydrazinyladenosine derivatives as A2A adenosine receptor ligands
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To obtain potential A2A adenosine receptor agonists, a series of 2-hydrazinyladenosine derivatives were synthesized and assayed for adenosine receptors activity using radioligand binding activity assays. The binding activity of the subtypes was examined, and the structure-activity relationship of this class of compounds at the A2A receptor was investigated. A fragment-based computer-aided design method was used to modify the 2-position side chain structures with different structural fragments, and the newly generated molecules were docked to the A2A receptor to assess scoring and screening activity. To synthesize compounds with better scoring activity, the newly synthesized compounds were tested for in vitro receptor binding activity. 2-Hydrazinyladenosine derivatives of 32 new structural types were designed and synthesized, with the most potent adenosine derivative 23 exhibiting a Ki value of 1.8 nM for A2AAR and significant selectivity for the A2A receptor compared to the A1 receptor. In addition to, compound 23, 24, 30, 31, and 42 also exhibited potent A2A receptor selectivity, with Ki values for the A2A receptor of 6.4, 20, 67 and 6.3 nM, respectively. We also found that compound 35 has a high A1 receptor selectivity, with a Ki value for the A1 receptor of 4.5 nM. Further functional assays also demonstrated that these compounds have potent A2A receptor agonist activity. The study shows the applicability of an in silico fragment-based molecular design for rational lead optimization in A2AAR.
- Zhang, Min,Fan, Shiyong,Zhou, Xinbo,Xie, Fei,Li, Song,Zhong, Wu
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p. 310 - 324
(2019/07/02)
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- Modified adenosine receptor agonist nano probe and its preparation and use
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The invention belongs to the biomedical field, and relates to a modification adenosine receptor agonist nanoprobe, and a production method and a use thereof. The general formula of the nanoprobe is IR783-Den-(PEG-Reg)x, wherein Den is a probe vector fifth-generation polyamidoamine dendrimer; IR783 is a near infrared fluorescent group, and PEG is polyethylene glycol with the molecular weight of 10-40k; and Reg is an adenosine A2A receptor specific agonist Regadenason, and x is the number of PEGReg marked on a probe. In the invention, one end of difunctional polyethylene glycol (Mal-PEG-NHS) is connected with the probe vector Den through a maleimide group, and the other end is connected with the adenosine receptor agonist Reg through an N-hydroxysuccinimidyl group. The quantity of the adenosine receptor agonist modified on the surface of the probe is adjusted by controlling a feeding ratio. The modification adenosine receptor agonist nanoprobe is of great research and clinical significance to improving the brain disease treatment effect, reducing the toxic side effects in the treatment process and promoting the clinic transformation of the individualized treatment schemes of brain diseases.
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Paragraph 0037; 0038
(2018/08/03)
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- Discovery of novel purine nucleoside derivatives as phosphodiesterase 2 (PDE2) inhibitors: Structure-based virtual screening, optimization and biological evaluation
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Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC50 = 3.12 ± 0.67 μM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC50 = 0.32 ± 0.04 μM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5′-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors.
- Qiu, Xiaoxia,Huang, Yiyou,Wu, Deyan,Mao, Fei,Zhu, Jin,Yan, Wenzhong,Luo, Hai-Bin,Li, Jian
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p. 119 - 133
(2017/11/30)
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- Synthetic method of 2-(3,3,3-trifluoropropylthio) adenosine
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The invention belongs to the field of medicinal chemistry synthesis and discloses a synthetic method of 2-(3,3,3-trifluoropropylthio) adenosine. The method comprises the following steps: firstly performing nucleophilic substitution between 2-Chloroadenine (as shown in a formula I) as a raw material and tetraacetylribofuranose in a first solvent under a function of catalyst SnCl4 to obtain a compound (as shown in a formula II); performing hydrolysis reaction on the compound (as shown in the formula II) in a second solvent under a function of alkali a to obtain a compound (as shown in formula a III); finally performing nucleophilic substitution on the compound (as shown in the formula III) and 3,3,3-trifluoro-propanethiol under a function of alkali b to obtain a compound (as shown in a formula IV), namely 2-(3,3,3-trifluoropropylthio) adenosine. The synthetic method in the invention is simple in lines, high in yield and low in cost, and raw materials are low in cost and easy to obtain.
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- METHOD FOR THE SYNTHESIS OF CLOFARABINE
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The present invention relates to a method for the high yield production of the anticancer nucleoside clofarabine, the method comprising the preparation of 2-chloroadenosine by enzymatic transglycosylation between 2-chloroadenine and nucleosides, benzoylation, isomerization, sulfonate ester formation, fluorination, and deprotection.
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Paragraph 0058
(2017/04/11)
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- Novel Polymorph of Regadenoson
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The invention provides a novel polymorph of Regadenoson. More particularly, the invention provides propylene glycol solvate of Regadenoson. The invention also provides a process for the preparation of propylene glycol solvate of Regadenoson.
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Paragraph 0042
(2016/05/19)
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- Novel Process for the Preparation of (1-pyrazole-4-yl)-N-methylcarboxamide
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The present invention relates to a novel process for the preparation of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide.
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Paragraph 0026
(2015/12/30)
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- Cladribine analogues via O6-(benzotriazolyl) derivatives of guanine nucleosides
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Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.
- Satishkumar, Sakilam,Vuram, Prasanna K.,Relangi, Siva Subrahmanyam,Gurram, Venkateshwarlu,Zhou, Hong,Kreitman, Robert J.,Montemayor, Michelle M. Martínez,Yang, Lijia,Kaliyaperumal, Muralidharan,Sharma, Somesh,Pottabathini, Narender,Lakshman, Mahesh K.
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p. 18437 - 18463
(2015/11/11)
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- Synthesis of 2,6-dihalogenated purine nucleosides by thermostable nucleoside phosphorylases
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The enzymatic transglycosylation of 2,6-dichloropurine (26DCP) and 6-chloro-2-fluoropurine (6C2FP) with uridine, thymidine and 1-(β-D-arabinofuranosyl)-uracil as the pentofuranose donors and recombinant thermostable nucleoside phosphorylases from G. thermoglucosidasius or T. thermophilus as biocatalysts was studied. Selection of 26DCP and 6C2FP as substrates is determined by their higher solubility in aqueous buffer solutions compared to most natural and modified purines and, furthermore, synthesized nucleosides are valuable precursors for the preparation of a large number of biologically important nucleosides. The substrate activity of 26DCP and 6C2FP in the synthesis of their ribo- and 2′-deoxyribo-nucleosides was closely similar to that of related 2-amino- (DAP), 2-chloro- and 2-fluoroadenines; the efficiency of the synthesis of β-D-arabinofuranosides of 26DCP and 6C2FP was lower vs. that of DAP under similar reaction conditions. For a convenient and easier recovery of the biocatalysts, the thermostable enzymes were immobilized on MagReSyn epoxide beads and the biocatalyst showed high catalytic efficiency in a number of reactions. As an example, 6-chloro-2-fluoro-(β-D-ribofuranosyl)-purine (9), a precursor of various antiviral and antitumour drugs, was synthesized by the immobilized enzymes at 60°C under high substrate concentrations (uridine:purine ratio of 2:1, mol). The synthesis was successfully scaled-up [uridine (2.5 mmol), base (1.25 mmol); reaction mixture 50 mL] to afford 9 in 60% yield. The reaction reveals the great practical potential of this enzymatic method for the efficient production of modified purine nucleosides of pharmaceutical interest.
- Zhou, Xinrui,Szeker, Kathleen,Jiao, Lin-Yu,Oestreich, Martin,Mikhailopulo, Igor A.,Neubauer, Peter
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p. 1237 - 1244
(2015/04/22)
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- The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: The electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases
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Two approaches to the synthesis of 2-chloro-9-(2-deoxy-2-fluoro-β-D- arabinofuranosyl)adenine (1, clofarabine) were studied. The first approach consists in the chemical synthesis of 2-deoxy-2-fluoro-α-D- arabinofuranose-1-phosphate (12a, 2FAra-1P) via three step conversion of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose (9) into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP) resulted in the formation of clofarabine in 67% yield. The reaction was also studied with a number of purine bases (2-aminoadenine and hypoxanthine), their analogues (5-aza-7-deazaguanine and 8-aza-7- deazahypoxanthine) and thymine. The results were compared with those of a similar reaction with α-D-arabinofuranose-1-phosphate (13a, Ara-1P). Differences of the reactivity of various substrates were analyzed by ab initio calculations in terms of the electronic structure (natural purines vs analogues) and stereochemical features (2FAra-1P vs Ara-1P) of the studied compounds to determine the substrate recognition by E. coli nucleoside phosphorylases. The second approach starts with the cascade one-pot enzymatic transformation of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a, followed by its condensation with 2-chloroadenine thereby affording clofarabine in ca. 48% yield in 24 h. The following recombinant E. coli enzymes catalyze the sequential conversion of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a: ribokinase (2-deoxy-2-fluoro-D-arabinofuranose-5-phosphate), phosphopentomutase (PPN; no 1,6-diphosphates of D-hexoses as co-factors required) (12a), and finally PNP. The substrate activities of D-arabinose, D-ribose and D-xylose in the similar cascade syntheses of the relevant 2-chloroadenine nucleosides were studied and compared with the activities of 2-deoxy-2-fluoro-D-arabinose. As expected, D-ribose exhibited the best substrate activity [90% yield of 2-chloroadenosine (8) in 30 min], D-arabinose reached an equilibrium at a concentration of ca. 1:1 of a starting base and the formed 2-chloro-9-(β-D- arabinofuranosyl) adenine (6) in 45 min, the formation of 2-chloro-9-(β-D- xylofuranosyl)adenine (7) proceeded very slowly attaining ca. 8% yield in 48 h.
- Fateev, Ilja V.,Antonov, Konstantin V.,Konstantinova, Irina D.,Muravyova, Tatyana I.,Seela, Frank,Esipov, Roman S.,Miroshnikov, Anatoly I.,Mikhailopulo, Igor A.
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p. 1657 - 1669
(2014/10/15)
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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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p. 436 - 447
(2013/03/14)
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- Regiospecific and highly stereoselective coupling of 6-(substituted- imidazol-1-yl)purines with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro- pentofuranosyl chloride. Sodium-salt glycosylation in binary solvent mixtures: Improved synthesis of cladribine
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(Chemical Equation Presented) Glycosylation of 6-(substituted-imidazol-1- yl)purine sodium salts with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro- pentofuranosyl chloride proceeds with regiospecific formation of the N9 isomers. Base substrates with lipophilic substituents on the C6-linked imidazole moiety are more soluble in organic solvents, and the solubility is further increased with binary solvent mixtures. Selective solvation also diminishes the extent of anomerization of the chlorosugar. Stirred reaction mixtures of the modified-purine sodium salts generated in a polar solvent and cooled solutions of the protected 2-deoxysugar chloride in a nonpolar solvent give 2′-deoxynucleoside derivatives with N9 regiochemistry and enhanced β/α configuration ratios. Application of the binary-solvent methodology with 2-chloro-6-(substituted-imidazol-1-yl)purine salts in cold acetonitrile and the chlorosugar in cold dichloromethane gives essentially quantitative yields of the N9 isomers of β-anomeric 2′- deoxynucleoside intermediates. Direct ammonolysis (NH3MeOH) of such intermediates or benzylation of the imidazole ring followed by milder ammonolysis of the imidazolium salt gives high yields of the clinical anticancer drug cladribine (2-chloro-2′-deoxyadenosine).
- Zhong, Minghong,Nowak, Ireneusz,Robins, Morris J.
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p. 7773 - 7779
(2007/10/03)
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- Azido/Tetrazole Tautomerism in 2-Azidoadenine β -D-Pentofuranonucleoside Derivatives
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The β-D-ribofuranoside derivative of 2-azidoadenine and its 2′-deoxy-, 2′,3′-dideoxy- and 2′,3′ -dideoxy-2′,3′-didehydro counterparts have been synthesized. All these compounds were obtained through the preparation of their 2-chloro precursors. These were converted into their 2-hydrazino derivatives, which upon treatment with sodium nitrate in acid medium gave the target nucleosides. The azido/tetrazole tautomerism observed in such nucleoside analogues was studied in detail. The compounds were also tested for their activity against HIV and HBV, but did not show significant antiviral effects. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Lioux, Thierry,Gosselin, Gilles,Mathe, Christophe
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p. 3997 - 4002
(2007/10/03)
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- Anti-HCV nucleoside derivatives
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The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.
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- 2-(purin-9-yl)-tetrahydrofuran-3, 4-diol derivatives
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There are disclosed according to the invention, compounds of formula (I) wherein R1, R2and R3are defined in the specification. Additionally, processes of preparing the compounds of formula (I), formulations containing same, and the administration of said compounds or formulations thereof in the treatment of inflammatory diseases are also disclosed.
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- Specific lipid conjugates to nucleoside diphosphates and their use as drugs
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The present invention concerns new phospholipid derivatives of nucleosides of the general formula (I) in which R1represents a straight-chained or branched, saturated or unsaturated aliphatic residue with 9-14 carbon atoms which can optionally be substituted once or several times; R2can represent a straight-chained or branched, saturated or unsaturated aliphatic residue with 8-12 carbon atoms which can optionally be substituted once or several times; m is 2 or 3; A can represent a methylene group or an oxygen; Nuc can be a nucleoside or a residue derived from a nucleoside derivative; and tautomers thereof and their physiologically tolerated salts of inorganic and organic acids and bases as well as pharmaceutical preparations containing these compounds.
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- Lipid esters of nucleoside monophosphates and their use as immunosuppressive drugs
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The present invention is directed to new nucleoside monophosphate derivatives of lipid ester residues of general formula (I) wherein R1 represents an optionally substituted alkyl chain having 1-20 carbon atoms; R2 represents hydrogen, an optionally substituted alkyl chain having 1-20 carbon atoms; R3, R4 and R5 represent hydrogen, hydroxy, azido, amino, cyano, or halogen; X represents a valence dash, oxygen, sulfur, a sulfinyl or sulfonyl group; Y represents a valence dash, an oxygen or sulfur atom; B represents a purine and/or pyrimidine base; with the proviso that at least one of the residues R3 or R5 is hydrogen; to their tautomers and their physiologically acceptable salts of inorganic and organic acids and/or bases, as well as to processes for their preparation, and to drugs containing said compounds.
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- Intermediates useful in a synthesis of 2-chloro-2'-deoxyadenosine
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This invention relates to a novel process for preparing 2-chloro-2'-deoxyadenosine (2-CdA) having the following formula STR1 from a compound of the following formula STR2 The invention also relates to intermediates which are useful in preparing 2-CdA. The compound 2-CdA is useful as an antileukemic agent, i.e., in treating leukemias, such as hairy cell leukemia.
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- Anti-dementia agents
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An anti-dementia agent comprising as an active ingredient an adenosine derivative is disclosed. The anti-dementia agent is useful in the therapy of various types of dementia, especially senile dementia. Examples of the adenosine derivative include L-N6 -phenylisopropyl-adenosine, 2-chloroadenosine, N6 -cyclohexyladenosine, adenosine-5'-(N-cyclopropyl)carboxamide.
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- 2-(SUBSTITUTED AMINO) ADENOSINES AS ANTIHYPERTENSIVES
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Disclosed are 2-substituted adenosine derivatives of the formula STR1 in which R represents a substituted amino grouping of the formula STR2 as defined herein; pharmaceutically acceptable ester derivatives thereof in which free hydroxy groups are esterified in the form of a pharmaceutically acceptable prodrug ester; and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for their preparation; and their use in mammals as therapeutically effective adenosine-2 (A-2) agonists.
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- Novel adenosine derivatives and pharmaceutical composition containing them as an active ingredient
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Novel adenosine compounds of the formula (I): STR1 wherein R1, R2 and R3 are hydrogen or a lower alkyl group; X is hydrogen, a lower alkyl group, an amino group or halogen; and Y is hydrogen or a lower alkyl group, exhibit utility as antihypertensive agents.
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- S-substituted-2-thioadenosines
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S-Substituted-2-thioadenosines represented by the formula (I): SPC1 wherein R is as defined hereinafter, useful as a platelet aggregation inhibitor and a coronary vasodilator.
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