696-07-1Relevant academic research and scientific papers
Electrochemical Synthesis of 5-Selenouracil Derivatives by Selenylation of Uracils
Chen, Yan-Yan,Jiang, Cai-Na,Ma, Xian-Li,Wang, Qian,Xu, Yan-Li
, (2020)
A simple and efficient electrochemical selenylation of uracils in the presence of NH4I for the synthesis of 5-selenouracils has been developed. This transformation was performed in the transition metal-free, oxidant-free, and aerobic conditions, providing a rapid and practical protocol to 5-selenouracil derivatives.
The Peculiar Case of the Hyper-thermostable Pyrimidine Nucleoside Phosphorylase from Thermus thermophilus**
Kaspar, Felix,Neubauer, Peter,Kurreck, Anke
, p. 1385 - 1390 (2021/01/29)
The poor solubility of many nucleosides and nucleobases in aqueous solution demands harsh reaction conditions (base, heat, cosolvent) in nucleoside phosphorylase-catalyzed processes to facilitate substrate loading beyond the low millimolar range. This, in turn, requires enzymes that can withstand these conditions. Herein, we report that the pyrimidine nucleoside phosphorylase from Thermus thermophilus is active over an exceptionally broad pH (4–10), temperature (up to 100 °C) and cosolvent space (up to 80 % (v/v) nonaqueous medium), and displays tremendous stability under harsh reaction conditions with predicted total turnover numbers of more than 106 for various pyrimidine nucleosides. However, its use as a biocatalyst for preparative applications is critically limited due to its inhibition by nucleobases at low concentrations, which is unprecedented among nonspecific pyrimidine nucleoside phosphorylases.
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.).
Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design to Minimize Host Kinase Interactions
Wang, Tiansheng,Bemis, Guy,Hanzelka, Brian,Zuccola, Harmon,Wynn, Michael,Moody, Cameron Stuver,Green, Jeremy,Locher, Christopher,Liu, Aixiang,Gao, Hongwu,Xu, Yuzhou,Wang, Shaohui,Wang, Jie,Bennani, Youssef L.,Thomson, John A.,Müh, Ute
supporting information, p. 1224 - 1229 (2017/12/26)
Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (Ki ≈ 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 μM (1-2 μg/mL) against the H37Ra isolate of M. tuberculosis.
Design and development of macrocyclization methods for compounds with potential tuberculocidal activity to decrease CYP450 liver cytochrome inhibition
Vasilevich,Aksenova,Aksenova,Afanasyev
, p. 717 - 730 (2017/05/29)
A procedure for macrocyclization of compounds with potential tuberculocidal activity was developed in order to obtaining compounds with a lower degree of inhibition of the key CYP 3A4 cytochrome.
Direct Arylation of 5-Iodouracil and 5-Iodouridine with Heteroarenes and Benzene via Photochemical Reaction
Yang, Qian,Wei, Tao,He, Yun,Liang, Yong,Zhang, Zun-Ting
, p. 953 - 960 (2015/11/23)
A method for the direct arylation of 5-iodouracil and 5-iodouridine was found to proceed in moderate yields. By irradiating mixtures of 5-iodouracil or 5-iodouridine and a series of five-membered heterocycles such as 1H-pyrrole, furan, 2-methylfuran, 1-methyl-1H-pyrrole, thiophene, as well as benzene in MeCN/H2O with a Hg lamp, 5-aryluracils and 5-aryluridines were synthesized. The reaction proceeded smoothly without the requirement of adding any transition metals or ligands.
5-Triazolyluracils and their N1-sulfonyl derivatives: Intriguing reactivity differences in the sulfonation of triazole N1′-substituted and N1′-unsubstituted uracil molecules
Saftic, Dijana,Vianello, Robert,?inic, Biserka
, p. 7695 - 7704 (2015/12/31)
We describe the synthesis of novel C5-triazolyl derived N1-sulfonylpyrimidines through CuI-catalyzed alkyne-azide cycloaddition followed by sulfonylation of the formed C5-triazolyl derivatives with various sulfonyl chlorides under basic conditions. In the latter step, an intriguing difference in the reactivity of the pyrimidine N1 was observed that depended on the nature of the substituent at a distant triazole N1′ site. The N1′-unsubstituted compounds gave very small amounts of sulfonylation products, whereas N1′-substituted systems produced high yields of the respective N1-sulfonyl-5-(1,2,3-triazol-4-yl)uracils. Computational analysis revealed a close correlation between the strength of the employed base catalysts and their abilities to increase the nucleophilicity of the uracil N1 atom through subsequent deprotonation, leading to more products. Following this step, the phosphazene tBu-P4 superbase was applied in the sulfonylation, resulting in exclusive formation of the triazole N1′-unsubstituted N1-sulfonylpyrimidines. The synthesis of C5-triazolyl-substituted pyrimidines and C5-triazolyl derived N1-sulfonylpyrimidines is described. Computational studies of the sulfonation step shed light on the differences in reactivity and revealed a connection between the strength of the employed base and its tendency to increase the nucleophilicity of the reacting uracil N1 atom by deprotonation.
Characterization of pyrimidine nucleoside phosphorylase of Mycoplasma hyorhinis: Implications for the clinical efficacy of nucleoside analogues
Vande Voorde, Johan,Gago, Federico,Vrancken, Kristof,Liekens, Sandra,Balzarini, Jan
experimental part, p. 113 - 123 (2012/10/23)
In the present paper we demonstrate that the cytostatic and antiviral activity of pyrimidine nucleoside analogues is markedly decreased by a Mycoplasma hyorhinis infection and show that the phosphorolytic activity of the mycoplasmas is responsible for this. Since mycoplasmas are (i) an important cause of secondary infections in immunocompromised (e.g. HIV infected) patients and (ii) known to preferentially colonize tumour tissue in cancer patients, catabolic mycoplasma enzymesmay compromise efficient chemotherapy of virus infections and cancer. In the genome of M. hyorhinis, a TP (thymidine phosphorylase) gene has been annotated. This gene was cloned, expressed in Escherichia coli and kinetically characterized. Whereas the mycoplasma TP efficiently catalyses the phosphorolysis of thymidine (Km = 473 μM) and deoxyuridine (Km = 578 μM), it prefers uridine (K m =92 μM) as a substrate. Our kinetic data and sequence analysis revealed that the annotated M. hyorhinis TP belongs to the NP (nucleoside phosphorylase)-II class PyNPs (pyrimidine NPs), and is distinct from the NP-II class TP and NPI class UPs (uridine phosphorylases). M. hyorhinis PyNP also markedly differs from TP and UP in its substrate specificity towards therapeutic nucleoside analogues and susceptibility to clinically relevant drugs. Several kinetic properties of mycoplasma PyNP were explained by in silico analyses. The Authors Journal compilation
Rigid rod and tetrahedral hybrid compounds featuring nucleobase and nucleoside End-capped structures
Schindler, Diana,Eissmann, Frank,Weber, Edwin
experimental part, p. 3549 - 3560 (2010/01/06)
Being aimed at a new type of porous solids, a moduled design strategy of molecular tectons, making use of the conjugation between a shape defined artificial backbone and the bioinspired molecular fragments of nucleobases or nucleobase derivatives as functional end-caps, has been developed. This led to the formation of the new hybrid compounds 1-13 of linear and tetrahedral geometry, containing uracil, adenine, adenosine, guanosine and its acylated analogs as the sticky end-cap sites. The compounds were synthesized from a halogen or ethynyl substituted nucleobase component and the corresponding ethynylated spacer unit following a metal assisted coupling process as the key reaction step. X-Ray crystal structure analysis demonstrates that the parent compound 1 is a solvent complex with DMSO (1:2), showing the DMSO molecules incorporated in a hydrogen bonded layer structure. Specific dependencies of the fluorescence properties of the new compounds in solution on the structure of the molecules are reported. A selection of solid compounds has been studied in respect of their ability to adsorb organic vapours. They revealed significant differences both in the sorption capacity and the selectivity towards particular solvent vapours.
COMPOSITIONS AND METHODS FOR INHIBITING SPHINGOSINE KINASE
-
, (2009/12/27)
Amidine analogs that can inhibit the activity of sphingosine kinase 1 and sphingosine kinase 2 (SphK1 and SphK2) are provided. The compounds can prevent angiogenesis in tumor cells.
