- Hypobromous acid, a powerful endogenous electrophile: Experimental and theoretical studies
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Abstract Hypobromous acid (HOBr) is an inorganic acid produced by the oxidation of the bromide anion (Br-). The blood plasma level of Br- is more than 1,000-fold lower than that of chloride anion (Cl-). Consequently, the endogenous production of HOBr is also lower compared to hypochlorous acid (HOCl). Nevertheless, there is much evidence of the deleterious effects of HOBr. From these data, we hypothesized that the reactivity of HOBr could be better associated with its electrophilic strength. Our hypothesis was confirmed, since HOBr was significantly more reactive than HOCl when the oxidability of the studied compounds was not relevant. For instance: anisole (HOBr, k2 = 2.3 × 102 M- 1 s- 1, HOCl non-reactive); dansylglycine (HOBr, k2 = 7.3 × 106 M- 1 s- 1, HOCl, 5.2 × 102 M- 1 s- 1); salicylic acid (HOBr, k2 = 4.0 × 104 M- 1 s- 1, non-reactive); 3-hydroxybenzoic acid (HOBr, k2 = 5.9 × 104 M- 1 s- 1, HOCl, k2 = 1.1 × 101 M- 1 s- 1); uridine (HOBr, k2 = 1.3 × 103 M- 1 s- 1, HOCl non-reactive). The compounds 4-bromoanisole and 5-bromouridine were identified as the products of the reactions between HOBr and anisole or uridine, respectively, i.e. typical products of electrophilic substitutions. Together, these results show that, rather than an oxidant, HOBr is a powerful electrophilic reactant. This chemical property was theoretically confirmed by measuring the positive Mulliken and ChelpG charges upon bromine and chlorine. In conclusion, the high electrophilicity of HOBr could be behind its well-established deleterious effects. We propose that HOBr is the most powerful endogenous electrophile.
- Ximenes, Valdecir Farias,Morgon, Nelson Henrique,De Souza, Aguinaldo Robinson
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Read Online
- The synthesis and antituberculosis activity of 5-alkynyl uracil derivatives
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A series of new 5-alkynyl-substituted uracil and uridine derivatives were synthesised via palladium-catalysed Sonogashira cross-coupling reaction of 5-bromo-pyrimidine base with terminal acetylenes with good yields in DMF at room temperature. All obtained compounds were tested for antimycobacterial activity against Mycobacetrium bovis and Mycobacterium tuberculosis (H37Ra) at concentrations of 1–100 μg/ml using MABA test. Obtained results revealed that most of tested uracil derivatives exhibited high antimycobacterial activity (MIC50 = 1.1–19.2 μg/ml) in comparison with therapeutic agents such as rifampicin, isoniazid and D-cycloserine, excluding compounds having alkyl substituent at triple alkyne bond.
- Platonova, Yana B.,Tomilova, Larisa G.,Volov, Alexander N.
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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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supporting information
p. 867 - 876
(2020/01/24)
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- Use of nucleoside phosphorylases for the preparation of 5-modified pyrimidine ribonucleosides
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Enzymatic transglycosylation, a transfer of the carbohydrate moiety from one heterocyclic base to another, is catalyzed by nucleoside phosphorylases (NPs) and is being actively developed and applied for the synthesis of biologically important nucleosides. Here, we report an efficient one-step synthesis of 5-substitited pyrimidine ribonucleosides starting from 7-methylguanosine hydroiodide in the presence of nucleoside phosphorylases (NPs).
- Alexeev, Cyril S.,Drenichev, Mikhail S.,Dorinova, Evgeniya O.,Esipov, Roman S.,Kulikova, Irina V.,Mikhailov, Sergey N.
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- SYNTHESIS AND STRUCTURE OF HIGH POTENCY RNA THERAPEUTICS
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This invention provides expressible polynucleotides, which can express a target protein or polypeptide. Synthetic mRNA constructs for producing a protein or polypeptide can contain one or more 5′ UTRs, where a 5′ UTR may be expressed by a gene of a plant. In some embodiments, a 5′ UTR may be expressed by a gene of a member of Arabidopsis genus. The synthetic mRNA constructs can be used as pharmaceutical agents for expressing a target protein or polypeptide in vivo.
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- ALTERNATIVE NUCLEIC ACID MOLECULES AND USES THEREOF
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The present disclosure provides alternative nucleosides, nucleotides, and nucleic acids, and methods of using them.
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Page/Page column 621
(2016/06/15)
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- ALTERNATIVE NUCLEIC ACID MOLECULES AND USES THEREOF
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The present disclosure provides alternative nucleosides, nucleotides, and nucleic acids, and methods of using them.
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Page/Page column 629
(2016/06/28)
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- Alternative nucleic acid molecules and uses thereof
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The present disclosure provides alternative nucleosides, nucleotides, and nucleic acids, and methods of using them.
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Paragraph 2169; 2170
(2015/11/09)
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- Direct One-Pot Synthesis of Nucleosides from Unprotected or 5-O-Monoprotected d -Ribose
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New, improved methods to access nucleosides are of general interest not only to organic chemists but to the greater scientific community as a whole due their key implications in life and disease. Current synthetic methods involve multistep procedures employing protected sugars in the glycosylation of nucleobases. Using modified Mitsunobu conditions, we report on the first direct glycosylation of purine and pyrimidine nucleobases with unprotected d-ribose to provide β-pyranosyl nucleosides and a one-pot strategy to yield β-furanosides from the heterocycle and 5-O-monoprotected d-ribose.
- Downey, A. Michael,Richter, Celin,Pohl, Radek,Mahrwald, Rainer,Hocek, Michal
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p. 4604 - 4607
(2015/09/28)
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- MODIFIED NUCLEIC ACID MOLECULES AND USES THEREOF
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The present disclosure provides modified nucleosides, nucleotides, and nucleic acids, and methods of using them.
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Page/Page column 288; 289
(2014/07/07)
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- An efficient and facile methodology for bromination of pyrimidine and purine nucleosides with sodium monobromoisocyanurate (SMBI)
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An efficient and facile strategy has been developed for bromination of nucleosides using sodium monobromoisocyanurate (SMBI). Our methodology demonstrates bromination at the C-5 position of pyrimidine nucleosides and the C-8 position of purine nucleosides. Unprotected and also several protected nucleosides were brominated in moderate to high yields following this procedure.
- Maity, Jyotirmoy,Stromberg, Roger
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p. 12740 - 12750
(2013/11/06)
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- Bromination at C-5 of pyrimidine and C-8 of purine nucleosides with 1,3-dibromo-5,5-dimethylhydantoin
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Treatment of the protected and unprotected nucleosides with 1,3-dibromo-5,5-dimethylhydantoin in aprotic solvents such as CH 2Cl2, CH3CN, or DMF effected smooth bromination of uridine and cytidine derivatives at C-5 of pyrimidine rings as well as adenosine and guanosine derivatives at C-8 of purine rings. Addition of Lewis acids such as trimethylsilyl trifluoromethanesulfonate enhanced the efficiency of bromination.
- Rayala, Ramanjaneyulu,Wnuk, Stanislaw F.
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experimental part
p. 3333 - 3336
(2012/07/30)
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- Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation
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Five ribofuranosyl pyrimidine nucleosides and their corresponding 1,2,3-triazole derivatives have been synthesized and characterized. Their inhibitory action to Ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are potent competitive inhibitors of RNase A with low μM inhibition constant (Ki) values with the ones having a triazolo linker being more potent than the ones without. The most potent of these is 1-[(β-d-ribofuranosyl)-1,2,3-triazol-4-yl]uracil being with Ki = 1.6 μM. The high resolution X-ray crystal structures of the RNase A in complex with three most potent inhibitors of these inhibitors have shown that they bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B1 subsite while the triazole moiety binds at the main subsite P1, where P-O5′ bond cleavage occurs, and the ribose at the interface between subsites P1 and P0 exploiting interactions with residues from both subsites. The effect of a susbsituent group at the 5-pyrimidine position at the inhibitory potency has been also examined and results show that any addition at this position leads to a less efficient inhibitor. Comparative structural analysis of these RNase A complexes with other similar RNase A - ligand complexes reveals that the triazole moiety interactions with the protein form the structural basis of their increased potency. The insertion of a triazole linker between the pyrimidine base and the ribose forms the starting point for further improvement of these inhibitors in the quest for potent ribonucleolytic inhibitors with pharmaceutical potential.
- Parmenopoulou, Vanessa,Chatzileontiadou, Demetra S.M.,Manta, Stella,Bougiatioti, Stamatina,Maragozidis, Panagiotis,Gkaragkouni, Dimitra-Niki,Kaffesaki, Eleni,Kantsadi, Anastassia L.,Skamnaki, Vassiliki T.,Zographos, Spyridon E.,Zounpoulakis, Panagiotis,Balatsos, Nikolaos A.A.,Komiotis, Dimitris,Leonidas, Demetres D.
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p. 7184 - 7193
(2013/01/15)
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- Highly efficient method for C-5 halogenation of pyrimidine-based nucleosides in ionic liquids
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A novel, highly efficient, convenient, and benign methodology for C-5 halogenation of pyrimidine-based nucleosides has been developed using N-halosuccinimides as halogenating reagents without using any catalyst in ionic liquid medium. The ionic liquids were successfully recovered and reused for all the reactions. Georg Thieme Verlag Stuttgart.
- Kumar, Vineet,Yap, Jeremy,Muroyama, Andrew,Malhotra, Sanjay V.
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experimental part
p. 3957 - 3962
(2010/03/26)
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- Ionic liquid mediated synthesis of 5-halouracil nucleosides: Key precursors for potential antiviral drugs
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Synthesis of antiviral 5-halouracil nucleosides, also used as key precursors for the synthesis of other potential antiviral drugs, has been demonstrated using ionic liquids as convenient and efficient reaction medium.
- Kumar, Vineet,Malhotra, Sanjay V.
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experimental part
p. 821 - 834
(2010/08/20)
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- Lys314 is a nucleophile in non-classical reactions of orotidine-5′- monophosphate decarboxylase
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Orotidine-5′-monophosphate decarboxylase (OMPD) catalyzes the decarboxylation of orotidine-5′-monophosphate (OMP) to uridine-5′-monophosphate (UMP) in an extremely proficient manner. The reaction does not require any cofactors and proceeds by an unknown mechanism. In addition to decarboxylation, OMPD is able to catalyze other reactions. We show that several C6-substituted UMP derivatives undergo hydrolysis or substitution reactions that depend on a lysine residue (Lys314) in the OMPD active site. 6-Cyano-UMP is converted to UMP, and UMP derivatives with good leaving groups inhibit OMPD by a suicide mechanism in which Lys314 covalently binds to the substrate. These non-classical reactivities of human OMPD were characterized by cocrystallization and freeze-trapping experiments with wildtype OMPD and two active-site mutants by using substrate and inhibitor nucleotides. The structures show that the C6-substituents are not coplanar with the pyrimidine ring. The extent of this substrate distortion is a function of the substituent geometry. Structurebased mechanisms for the reaction of 6-substituted UMP derivatives are extracted in accordance with results from mutagenesis, mass spectrometry, and OMPD enzyme activity. The Lys314based mechanisms explain the chemodiversity of OMPD, and offer a strategy to design mechanism-based inhibitors that could be used for antineoplastic purposes for example.
- Heinrich, Daniel,Diederichsen, Ulf,Rudolph, Markus Georg
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supporting information; experimental part
p. 6619 - 6625
(2010/03/03)
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- Novel derivatives of UDP-glucose: Concise synthesis and fluorescent properties
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A series of novel 5-substituted UDP-glucose derivatives with interesting fluorescent properties and potential applications as sensors for carbohydrate-active enzymes is reported. An efficient synthesis of the target molecules was developed, centred around the Suzuki-Miyaura reaction of (hetero)arylboronic acids with 5-iodo UDP-glucose. Interestingly, the optimised cross-coupling conditions could also be applied successfully to 5-bromo UMP, but not to 5-bromo UDP-glucose. The Royal Society of Chemistry.
- Pesnot, Thomas,Wagner, Gerd K.
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experimental part
p. 2884 - 2891
(2009/02/03)
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- CYTIDINE ANALOGS AND METHODS OF USE
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Cytidine analogs, their prodrugs and/or metabolites are employed as pharmaceutically active compounds for treatment of diseases responsive to such compounds. Particularly preferred diseases include viral diseases (e.g., HCV infection) and neoplasms.
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Page/Page column 21
(2010/02/08)
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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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- Synthesis, cytotoxic effect and antiviral activity of 1-(β-D- arabinofuranosyl)-5-bromo-N4-substituted cytosine and 1-(β-D- arabinofuranosyl)-5-bromo-4-methoxypyrimidin-2(1H)-one derivatives
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A convenient and mild synthesis of 5-bromo-N4-substituted-1-(β-D- arabinofuranosyl)cytosine and 5-bromo-O4-methyl-1-(β-D- arabinofuranosyl)pyrimidin-2(1H)-one derivatives by selective oxyfunctionalization of the corresponding 4-thionucleosides with 3,3- dimethyldioxirane is reported. The cytotoxicity and the antiviral activity against parainfluenza 1 (Sendai virus) of all new synthesized products are also reported.
- Saladino, Raffaele,Mezzetti, Maurizio,Mincione, Enrico,Palamara, Anna Teresa,Savini, Patrizia,Marini, Stefano
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p. 2499 - 2510
(2007/10/03)
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- A mild and efficient methodology for the synthesis of 5-halogeno uracil nucleosides that occurs via a 5-halogeno-6-azido-5,6-dihydro intermediate
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A mild and efficient methodology for the synthesis of 5-halogeno (iodo, bromo, or chloro) uracil nucleosides has been developed. 5-Halo-2'-deoxyuridines 4a-c (84-95%), 5-halouridines 7a-c (45-95%), and 5-haloarabinouridines 8a-c (65-95%) were synthesized in good to excellent yields by the reaction of 2'-deoxyuridine (2), uridine (5) and arabinouridine (6), respectively with iodine monochloride, or N-bromo (or chloro)succinimide, and sodium azide at 25-45°C. These C-5 halogenation reactions proceed via a 5-halo-6-azido-5,6-dihydro intermediate (3), from which HN3 is eliminated, to yield the 5-halogeno uracil nucleoside. The 5-halo-6-azido-5,6-dihydro intermediate products (10a, 10b) could be isolated from the reaction of 3',5'-di-O-acetyl-2'-deoxyuridine (9) with iodine monochloride or N-bromosuccinimide and sodium azide at 0°C. The isolation of 10a, 10b indicates that the C-5 halogenation reaction proceeds via a 5-halo-6-azido-5,6-dihydro intermediate.
- Kumar,Wiebe,Knaus
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p. 2005 - 2010
(2007/10/02)
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- Cerium(IV)-Mediated Halogenation at C-5 of Uracil Derivatives
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Treatment of protected uracil nucleosides 1 or 2 with elemental iodine or metal halogenides and ceric ammonium nitrate (CAN) at 80 deg C gave the corresponding protected 5-halouracil nucleosides 3a-f in excellent yields.Treatment of the resulting crude 3a-f with 0.1 M NaOMe/MeOH at ambient temperature gave the corresponding 5-halouridines 4a-f in high overall yields from 1 or 2.Further, 5-halouraciles 9a-f were prepared in good yields by treatment of 1,3-dimethyluracil (7) or uracil (8) with elemental iodine, metal halogenides, or hydrochloric acid and CAN.Halouridines 4a-e also were obtained in good yields by treatment of unprotected uracil nucleosides 5 or 6 with halogen sources as above and CAN.
- Asakura, Jun-ichi,Robins, Morris J.
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p. 4928 - 4933
(2007/10/02)
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- Reactions of 5-bromo substituted pyrimidine nucleosides with aqueous alkalies: kinetics and mechanisms.
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Kinetics for the parallel and consecutive steps of the reactions of 5-bromocytidine, 5-bromouridine and its 5'-O-methyl and 2',3'-O-isopropylidene derivatives with aqueous alkalies were studied by LC. The mechanisms of the partial reactions involved are discussed.
- K?ppi,L?nnberg
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p. 768 - 775
(2007/10/02)
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- The bromination and iodination of N1-substituted uracils
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Reaction of N1-substituted uracils with bromine in water at pH=7 leads to 5-bromo-6-hydroxy-5,6-hydrouracils.For different N1-substituents these products were isolated and the relatively stable derivatives were characterized by 1H NMR and mass spectroscopy.On electrophilic iodination with iodide and chloramine-T in water no indications were obtained for the formation of such dihydrouracils except for uridine and deoxyuridine.However, on reaction of N1-substituted uracils with N-iodosuccinimide in CHCl3 containing ethanol, or in ethanol, 5-iodo-6-ethoxy-5,6-dihydrouracils could be isolated as reaction products.
- Bakker, Cees N. M.,Kaspersen, Frans M.
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p. 267 - 271
(2007/10/02)
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