146-77-0Relevant academic research and scientific papers
Structure-Guided Tuning of a Selectivity Switch towards Ribonucleosides in Trypanosoma brucei Purine Nucleoside 2′-Deoxyribosyltransferase
Del Arco, Jon,Mills, Alberto,Gago, Federico,Fernández-Lucas, Jesús
, p. 2996 - 3000 (2019)
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.
Characterization of cladribine and its related compounds by high- performance liquid chromatography/mass spectrometry
Weber,Sampino,Dunphy,Burinsky,Williams,Motto
, p. 525 - 531 (1994)
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.
Protonation studies of modified adenine and adenine nucleotides by theoretical calculations and 15N NMR
Major, Dan T.,Laxer, Avital,Fischer, Bilha
, p. 790 - 802 (2002)
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.
2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5′-nucleotidase (CD73) Inhibitors with Variable Binding Modes
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
supporting information, p. 2941 - 2957 (2020/04/10)
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.
Thermodynamic Reaction Control of Nucleoside Phosphorolysis
Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
, p. 867 - 876 (2020/01/24)
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.).
General Principles for Yield Optimization of Nucleoside Phosphorylase-Catalyzed Transglycosylations
Kaspar, Felix,Giessmann, Robert T.,Hellendahl, Katja F.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
, p. 1428 - 1432 (2020/02/05)
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.
Design, synthesis and biological evaluation of 2-hydrazinyladenosine derivatives as A2A adenosine receptor ligands
Zhang, Min,Fan, Shiyong,Zhou, Xinbo,Xie, Fei,Li, Song,Zhong, Wu
, p. 310 - 324 (2019/07/02)
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.
Discovery of novel purine nucleoside derivatives as phosphodiesterase 2 (PDE2) inhibitors: Structure-based virtual screening, optimization and biological evaluation
Qiu, Xiaoxia,Huang, Yiyou,Wu, Deyan,Mao, Fei,Zhu, Jin,Yan, Wenzhong,Luo, Hai-Bin,Li, Jian
, p. 119 - 133 (2017/11/30)
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.
Modified adenosine receptor agonist nano probe and its preparation and use
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Paragraph 0037; 0038, (2018/08/03)
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.
Synthetic method of 2-(3,3,3-trifluoropropylthio) adenosine
-
, (2017/08/30)
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.
