1839-18-5Relevant articles and documents
Efficient chemo-enzymatic syntheses of pharmaceutically useful unnatural 2′-deoxynucleosides
Komatsu, Hironori,Araki, Tadashi
, p. 1127 - 1130 (2005)
Our chemo-enzymatic method was successfully applied to the synthesis of 2-chloro-2′-deoxyadenosine (CdA, cladribine) in two ways: 1) direct conversion of chemically synthesized 2-deoxy-α-D-ribose 1-phosphate (dRP) to CdA; 2) a two-step route via 9-(2-deoxy-β-D-ribos-1-yl)-2,6- dichloropurine (Cl2Pu-dR, 5). Copyright Taylor & Francis, Inc.
Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for Trypanosoma brucei Inhibitors
Singh, Baljinder,Diaz-Gonzalez, Rosario,Ceballos-Perez, Gloria,Rojas-Barros, Domingo I.,Gunaganti, Naresh,Gillingwater, Kirsten,Martinez-Martinez, Maria Santos,Manzano, Pilar,Navarro, Miguel,Pollastri, Michael P.
, p. 9912 - 9927 (2020)
Human African trypanosomiasis (HAT), or sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei and transmitted through the bite of infected tsetse flies. The disease is considered fatal if left untreated. To identify new chemotypes against Trypanosoma brucei, previously we identified 797 potent kinase-targeting inhibitors grouped into 59 clusters plus 53 singleton compounds with at least 100-fold selectivity over HepG2 cells. From this set of hits, a cluster of diaminopurine-derived compounds was identified. Herein, we report our medicinal chemistry investigation involving the exploration of structure-activity and structure-property relationships around one of the high-throughput screening (HTS) hits, N2-(thiophen-3-yl)-N6-(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine (1, NEU-1106). This work led to the identification of a potent lead compound (4aa, NEU-4854) with improved in vitro absorption, distribution, metabolism, and excretion (ADME) properties, which was progressed into proof-of-concept translation of in vitro antiparasitic activity to in vivo efficacy.
Thermodynamic Reaction Control of Nucleoside Phosphorolysis
Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
supporting information, 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.).
PURINE-SCAFFOLD TLR7 LIGANDS AND CONJUGATE THEREOF
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Paragraph 0092; 0093, (2017/12/18)
TLR7 ligands and conjugates thereof are useful in vaccines for prevention, inhibition or treatment of variety disorders, such as infection and cancer.
