- Bioactivation of food genotoxicants 5-hydroxymethylfurfural and furfuryl alcohol by sulfotransferases from human, mouse and rat: a comparative study
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5-Hydroxymethylfurfural (HMF) and furfuryl alcohol (FFA) are moderately potent rodent carcinogens that are present in thermally processed foodstuffs. The carcinogenic effects were hypothesized to originate from sulfotransferase (SULT)-mediated bioactivation yielding DNA-reactive and mutagenic sulfate esters, a confirmed metabolic pathway of HMF and FFA in mice. It is known that orthologous SULT forms substantially differ in substrate specificity and tissue distribution. This could influence HMF- and FFA-induced carcinogenic effects. Here, we studied HMF and FFA sulfoconjugation by 30 individual SULT forms of humans, mice and rats. The catalytic efficiencies (kcat/KM) of HMF sulfoconjugation of human SULT1A1 (13.7?s?1?M?1), mouse Sult1a1 (15.8?s?1?M?1) and 1d1 (4.8?s?1?M?1) and rat Sult1a1 (5.3?s?1?M?1) were considerably higher than those of all other SULT forms investigated (≤0.73?s?1M?1). FFA sulfoconjugation was monitored using adenosine as a nucleophilic scavenger for the reactive 2-sulfoxymethylfuran (t1/2?=?20?s at 37?°C). The resulting adduct N6-((furan-2-yl)methyl)-adenosine (N6-MF-A) was quantified by isotope-dilution UPLC-MS/MS. The rates of N6-MF-A formation showed that hSULT1A1 and its orthologues in mice and rats were also the most important contributors to FFA sulfoconjugation in each of the species. Taken together, the catalytic capacity of hSULT1A1 is comparable to that of mSult1a1 in mice, the species in which carcinogenic effects of HMF and FFA were detected. This is of primary concern due to the expression of hSULT1A1 in many different tissues.
- Sachse, Benjamin,Meinl, Walter,Sommer, Yasmin,Glatt, Hansruedi,Seidel, Albrecht,Monien, Bernhard H.
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Read Online
- Anion exchange resins in phosphate form as versatile carriers for the reactions catalyzed by nucleoside phosphorylases
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In the present work, we suggested anion exchange resins in the phosphate form as a source of phosphate, one of the substrates of the phosphorolysis of uridine, thymidine, and 1-(β-D-arabinofuranosyl)uracil (Ara-U) catalyzed by recombinant E. coli uridine (UP) and thymidine (TP) phosphorylases. α-D-Pentofuranose-1-phosphates (PF-1Pis) obtained by phosphorolysis were used in the enzymatic synthesis of nucleosides. It was found that phosphorolysis of uridine, thymidine, and Ara-U in the presence of Dowex 1X8 (phosphate; Dowex-nPi) proceeded smoothly in the presence of magnesium cations in water at 20-50 °C for 54-96 h giving rise to quantitative formation of the corresponding pyrimidine bases and PF-1Pis. The resulting PF-1Pis can be used in three routes: (1) preparation of barium salts of PF-1Pis, (2) synthesis of nucleosides by reacting the crude PF-1Pi with an heterocyclic base, and (3) synthesis of nucleosides by reacting the ionically bound PF-1Pi to the resin with an heterocyclic base. These three approaches were tested in the synthesis of nelarabine, kinetin riboside, and cladribine with good to excellent yields (52-93%).
- Artsemyeva, Julia N.,Buravskaya, Tatiana N.,Esipov, Roman S.,Konstantinova, Irina D.,Litvinko, Natalia M.,Mikhailopulo, Igor A.,Miroshnikov, Anatoly I.,Remeeva, Ekaterina A.
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p. 2607 - 2622
(2020/11/26)
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- Multinuclear magnetic resonance characterization and antiproliferative studies of novel dichlorido platinum(II) complexes containing kinetin riboside and 1-β-D-ribofuranosyl-4-(2-pyridyl)-1H-1,2,3-triazole
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The chemical reaction between cis-[PtCl2(dmso)2] and kinetin riboside (KR) or 1-β-D-ribofuranosyl-4-(2-pyridyl)-1H-1,2,3-triazole (PTR) has resulted in two novel platinum(II) complexes being obtained with different compositions of the coordination sphere: cis-[PtCl2(PTR)] (1) and cis-[PtCl2(dmso)(KR)] (2). Based on multinuclear NMR results (1H, 13C, 15N, 195Pt), we have demonstrated that the N-donor ligands PTR and KR are able to coordinate to the Pt(II) ion as bidentate via two nitrogen atoms (N(3) and N(7)) or monodentate via only one nitrogen atom (N(7)), respectively. On the other hand, biological studies showed that the novel platinum(II) complexes exhibit different in vitro cytotoxicity towards A549 (lung carcinoma epithelial cells), T24 (urinary bladder cancer cells) and CRL1872 (malignant melanoma cells). The complex cis-[PtCl2(dmso)(KR)] (2) shows in vitro cytotoxicity against T24 and CRL1872 cell lines (the IC50 parameters amount to 52.2 μM and 21.4 μM, respectively), whereas cis-[PtCl2(PTR)] (1) is not able to inhibit a proliferation of these cells in the range of tested concentrations.
- Jakubowski, Mateusz,?akomska, Iwona,Sitkowski, Jerzy,Pokrywczyńska, Marta,D?browski, Pawe?,Framski, Grzegorz,Ostrowski, Tomasz
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- New tools in nucleoside toolbox of tick-borne encephalitis virus reproduction inhibitors
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Design and development of nucleoside analogs is an established strategy in the antiviral drug discovery field. Nevertheless, for many viruses the coverage of structure-activity relationships (SAR) in the nucleoside chemical space is not sufficient. Here we present the nucleoside SAR exploration for tick-borne encephalitis virus (TBEV), a member of Flavivirus genus. Promising antiviral activity may be achieved by introduction of large hydrophobic substituents in the position 6 of adenosine or bulky silyl groups to the position 5′. Introduction of methyls to the ribose moiety does not lead to inhibition of TBEV reproduction. Possible mechanisms of action of these nucleosides include the inhibition of viral entry or interaction with TBEV non-structural protein 5 methyltransferase or RNA-dependent RNA polymerase domains.
- Orlov, Alexey A.,Drenichev, Mikhail S.,Oslovsky, Vladimir E.,Kurochkin, Nikolay N.,Solyev, Pavel N.,Kozlovskaya, Liubov I.,Palyulin, Vladimir A.,Karganova, Galina G.,Mikhailov, Sergey N.,Osolodkin, Dmitry I.
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supporting information
p. 1267 - 1273
(2017/06/19)
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- Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization
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Since loss of function mutations of PINK1 lead to early onset Parkinson’s disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability, and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.
- Osgerby, Laura,Lai, Yu-Chiang,Thornton, Peter J.,Amalfitano, Joseph,Le Duff, Cécile S.,Jabeen, Iqra,Kadri, Hachemi,Miccoli, Ageo,Tucker, James H. R.,Muqit, Miratul M. K.,Mehellou, Youcef
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p. 3518 - 3524
(2017/05/05)
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- APPLICATIONS OF N6-SUBSTITUTED ADENOSINE DERIVATIVE AND N6-SUBSTITUTED ADENINE DERIVATIVE TO CALMING, HYPNOSES, CONVULSION RESISTANCE, EPILEPTIC RESISTANCE, PARKINSON DISEASE RESISTANCE, AND DEMENTIA PREVENTION AND TREATMENT
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PROBLEM TO BE SOLVED: To prepare analgesics, hypnotic agents, anticonvulsant agents, antiepileptics, antiparkinson drugs, dementia prophylactics, and health care food. SOLUTION: The present invention relates to an N6-substituted adenosine derivative and an N6-substituted adenine derivative selected from the group consisting of specific compounds. The present invention also relates to a pharmaceutical composition at least comprising a therapeutically effective amount of the compounds and a pharmaceutically acceptable carrier. The invention further relates to the compounds used in preparation of analgesics, hypnotic agents, anticonvulsant agents, antiepileptics, antiparkinson drugs, dementia prophylactics, and health care food. COPYRIGHT: (C)2016,JPO&INPIT
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Paragraph 010
(2018/10/27)
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- N6-SUBSTITUTED ADENOSINE DERIVATIVES AND N6-SUBSTITUTED ADENINE DERIVATIVES AND USES THEREOF
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The present invention provides N6-substituted adenosine derivatives and N6-substituted adenine derivatives, manufacturing methods thereof, a pharmaceutical composition comprising the said compounds above, and uses of these compounds in manufacturing medicaments and health-care products for treating insomnia, convulsion, epilepsy, and Parkinson's diseases, and preventing and treating dementia.
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Paragraph 0136; 0139
(2013/03/26)
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- N6-SUBSTITUTED ADENOSINE DERIVATIVES, N6-SUBSTITUTED ADENINE DERIVATIVES AND USES THEREOF
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The present invention provides N6-substituted adenosine derivatives and N6-substituted adenine derivatives, manufacturing methods thereof, a pharmaceutical composition comprising the said compounds above, and uses of of these compounds in manufacturing medicaments and health-care products for treating insomnia, convulsion, epilepsy, and Parkinson's diseases, and preventing and treating dementia.
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- N6-acetyl-2,3,5-tri-O-acetyladenosine; A convenient, missed out substrate for regioselective N6-alkylations
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A simple and efficient route to N6-acetyl-2,3,5-tri-O- acetyladenosine (1) was developed based on selective N-deacetylation of pentaacetylated adenosine 2 with methanol at room temperature in the presence of imidazole. Preparative synthesis of 1 was elaborated utilizing a crude mixture of 2 and 1 which is produced by reaction of adenosine with acetic anhydride in pyridine at elevated temperatures. The total yield of 1 was 80-85% starting with adenosine. It was shown that 1 is a convenient substrate for selective N 6-alkylations. The study revealed the same regioselectivity in base-promoted reactions of 1 with activated alkyl halides and Mitsunobu reactions of 1 with alcohols. A series of N6-alkyladenosines 5a-f were prepared. Cytokinins 6b,d,e were prepared by enzymatic transformation of parent nucleoside derivatives 5b,d,e using a combination of nucleoside phosphorylase and alkaline phosphatase. Georg Thieme Verlag Stuttgart, New York.
- Tararov, Vitali I.,Kolyachkina, Svetlana V.,Alexeev, Cyril S.,Mikhailov, Sergey N.
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experimental part
p. 2483 - 2489
(2011/09/20)
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- N6-Substituted adenosines. Cytokinin and antitumor activities
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A series of N6-adenosine derivatives were synthesized by alkylation of N6-acetyl-2',3',5'-tri-O-acetyladenosine (1) with alkyl halides and alcohols. It was shown that propargyl derivative 2a is a good substrate for copper(I) catalyzed Huisgen [3+2] cycloaddition with azides. This click-reaction can be used for preparation of the libraries of 1,2,3-triazolyl modified adenosines. Biological activities of N6-adenosines were studied in two plant and six human cancer cell assays. The remarkable parallel between cytokinin and cytotoxic activities was found. The most cytokinin active compounds 3c-3e at the same time appeared to be the most potent cytotoxic agents.
- Kolyachkina, Svetlana V.,Tararov, Vitali I.,Alexeev, Cyril S.,Krivosheev, Dmitry M.,Romanov, Georgy A.,Stepanova, Evgenia V.,Solomko, Eliso S.,Inshakov, Andrey N.,Mikhailov, Sergey N.
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scheme or table
p. 1361 - 1378
(2012/04/04)
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- An enzymatic transglycosylation of purine bases
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An enzymatic transglycosylation of purine heterocyclic bases employing readily available natural nucleosides or sugar-modified nucleosides as donors of the pentofuranose fragment and recombinant nucleoside phosphorylases as biocatalysts has been investigated. An efficient enzymatic method is suggested for the synthesis of purine nucleosides containing diverse substituents at the C6 and C2 carbon atoms. The glycosylation of N6-benzoyladenine and N2-acetylguanine and its O6-derivatives is not accompanied by deacylation of bases. Copyright Taylor & Francis Group, LLC.
- Roivainen, Jarkko,Elizarova, Tatiana,Lapinjoki, Seppo,Mikhailopulo, Igor A.,Esipov, Roman S.,Miroshnikov, Anatoly I.
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p. 905 - 909
(2008/09/17)
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- A novel and facile reaction to N6-alkylated adenosine via benzotriazole as a synthetic auxiliary
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The reaction of benzotriazole with aliphatic, aromatic or heteroaromatic aldehyde and adenosine leads to a benzotriazole adduct which is reduced with sodium borohydride to the corresponding N6-alkylated adenosine derivatives. This procedure is also utilized in a new route to N6-(3- iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) which is considered an important adenosine agonist at A3 adenosine receptors.
- Afify, Hanan M. N. M.,Pedersen, Erik B.,Zahran, Magdy A.
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p. 339 - 341
(2007/10/03)
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- Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: Elucidation of a novel binding mode for a 2-Amino-N6-substituted adenosine
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As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N6-, 2-amino-N6-, and N2-substituted adenosine analogues were synthesized and tested to establish structure - activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for N6-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N6-[2-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 μM. 2-[[2-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 μM. To explore the potential of an additive effect that having the N6 and N2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N6,N2-disubstituted adenosine analogues to yield N6-(2-phenylethyl)-2-[(2-phenylethyl)amino]adenosine (69) as a 30 μM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 A? X-ray structure of a T. brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this 'flipped and rotated' binding mode.
- Bressi,Choe,HoughHough,Buckner,Van Voorhis,Verlinde,Hol,Gelb
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p. 4135 - 4150
(2007/10/03)
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- 1,N6-Etheno-Bridged Adenines and Adenosines. Alkyl Substitution, Fluorescence Properties, and Synthetic Applications
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It has been shown that the reaction of chloroacetaldehyde with adenosine at pH 4.5 and 37 deg C that produces the fluorescent ε-adenosine species will not develop interfering fluorescence with N6-alkyladenosines.The preferred site of methylation and benzylation of ε-adenosine and ε-adenine was established as N(9) (a) by acidic ring opening of the products to substituted aminobiimidazoles in which the two etheno protons were nonequivalent; (b) by reaction of N6-substituted adenines with chloroacetaldehyde followed by polyphosphoric acid to dehydrate the intermediate to an N(9)-substituted ε-adenine for an unequivocal synthesis.The fluorescence of the ε-adenosine and ε-adenine species at pH 7.0 has again been confirmed, and the fluorescence properties of their N(9)-alkylated derivatives under neutral and acidic conditions have been determined.It has been shown possible, earlier reports to the contrary, to prepare N6-substituted adenosines through Schiff-base formation on the 6-NH2.The general method involves the use of sodium cyanohydridoborate to bring about reductive amination of aldehydes and ketones at acidic pH and is exemplified by the synthesis of N6-ethyladenosine, N6-benzyladenosine, and N6-furfuryladenosine (kinetin riboside), using large excesses of aldehyde and reducing agent.
- Sattsangi, Prem D.,Barrio, Jorge R.,Leonard, Nelson J.
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p. 770 - 774
(2007/10/02)
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