- 8-Substituted, syn-Configured Adenosine Derivatives as Potential Inhibitors of the Enzyme IspE from the Non-Mevalonate Pathway of Isoprenoid Biosynthesis
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The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are attractive targets for drugs against various diseases, including malaria. We describe herein the structure-based design, synthesis, conformational analysis, and biological evaluation of several 8-brominated or 8-aminated adenosine derivatives with different substituents at C(5′), targeting the ATP-adenine binding site of the IspE protein from the non-mevalonate pathway. An exhaustive conformational analysis of the adenosine derivatives both in solution and in the solid state confirmed the desired syn orientation of the adenine moiety. Despite this favorable pre-organization for binding to the cofactor pocket, biological evaluation of the inhibitors showed only a very modest inhibitory activity.
- Harder, Michael,Sch?fer, Elisabeth,Kümin, Tobias,Illarionov, Boris,Bacher, Adelbert,Fischer, Markus,Diederich, Fran?ois,Bernet, Bruno
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p. 7276 - 7286
(2015/11/25)
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- Oxidation of adenosine and inosine: The chemistry of 8-Oxo-7,8- dihydropurines, purine iminoquinones, and purine quinones as observed by ultrafast spectroscopy
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Oxidative damage to purine nucleic acid bases proceeds through quinoidal intermediates derived from their corresponding 8-oxo-7,8-dihydropurine bases. Oxidation studies of 8-oxo-7,8-dihyroadenosine and 8-oxo-7,8-dihydroinosine indicate that these quinoidal species can produce stable cross-links with a wide variety of nucleophiles in the 2-positions of the purines. An azide precursor for the adenosine iminoquinone has been synthesized and applied in ultrafast transient absorption spectroscopic studies. Thus, the adenosine iminoquinone can be observed directly, and its susceptibility to nucleophilic attack with various nucleophiles as well as the stability of the resulting cross-linked species have been evaluated. Finally, these observations indicate that this azide might be a very useful photoaffinity labeling agent, because the reactive intermediate, adenosine iminoquinone, is such a good mimic for the universal purine base adenosine.
- Nilov, Denis I.,Komarov, Dmitry Y.,Panov, Maxim S.,Karabaeva, Kanykey E.,Mereshchenko, Andrey S.,Tarnovsky, Alexander N.,Wilson, R. Marshall
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supporting information
p. 3423 - 3438
(2013/05/08)
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- Radical reactions in aqueous medium using (Me3Si)3SiH
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(Chemical Equation Presented) (Me3Si)3SiH was used as a successful reagent in a variety of radical-based transformations in water. The system comprising substrate, silane, and initiator (ACCN) mixed in aqueous medium at 100°C worked well for both hydrophilic and hydrophobic substrates, with the only variation that an amphiphilic thiol was also needed in case of the water-soluble compounds.
- Postigo, Al,Kopsov, Sergey,Ferreri, Carla,Chatgilialoglu, Chryssostomos
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p. 5159 - 5162
(2008/09/17)
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- Kinetics and mechanism of the defluorination of 8-fluoropurine nucleosides in basic and acidic media
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For investigating the stability of C(8)-fluorine bond in 8-fluoropurine nucleosides some protected 8-fluoroguanosine, 8-fluoroinosine and 8-fluoroadenosine derivatives were prepared by direct fluorination of acetyl-protected purine nucleosides with elemental fluorine in solvents such as chloroform, acetonitrile and nitromethane. Fluorination reactions conducted in chloroform medium gave better yields of 8-fluoropurines. The fluorination yields were slightly lower when acetonitrile or nitromethane was used as solvent, but the product purification was found to be much easier. When the synthesized, protected fluoronucleosides were subjected to standard basic (NH3 in methanol or 2-propanol) and acidic (HCl in methanol) deprotection conditions relevant to nucleoside chemistry, an efficient defluorination reaction took place. The kinetics of these defluorination reactions were conveniently followed, under pseudo-first-order reaction conditions, using 19F NMR spectroscopy. 1H NMR, LC-MS and mass spectroscopy identified the products of the kinetic reaction mixtures. The defluorination reaction rate constants (kobs) in basic media depended upon the electron density at C(8) while the kobs data in acidic medium were determined by the pKa of N7. An addition-elimination based mechanism (SNAr) has been proposed for the defluorination reactions of these 8-fluoropurine nucleosides.
- Liu, Jie,Barrio, Jorge R.,Satyamurthy, Nagichettiar
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p. 1175 - 1187
(2008/12/20)
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- Convenient synthesis of 8-amino-2′-deoxyadenosine
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We studied the behaviour of 8-azido-2′-deoxyadenosine and 8-bromo-2′-deoxyadenosine in aqueous solutions of ammonia and primary and secondary amines. Unexpectedly, 8-Azido-2′-deoxyadenosine is converted to 8-amino-2′-deoxyadenosine in excellent yields. The use of this reaction for the preparation of 8-aminoadenine derivatives needed for the preparation of oligonucleotides carrying 8-aminoadenine is discussed.
- Frieden, Miriam,Avino, Anna,Eritja, Ramon
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p. 193 - 202
(2007/10/03)
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- Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
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The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.
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- H-phosphonate synthesis of oligoribonucleotides containing modified bases. I. Photoactivatable derivatives of oligoribonucleotides with perfluoroarylazide groups in heterocyclic bases
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H-phosphonate synthesis was proposed for oligoribonucleotides containing a bromine atom or an ethylenediamine linker at positions C5 or C8 of uridine or adenosine, respectively. Novel photoactivatable derivatives of oligoribonucleotides harboring a p-azidotetrafluorobenzoyl group attached to uridine or adenosine through the diamino linker were synthesized.
- Repkova,Ivanova,Komarova,Meshchaninova,Kuznetsova,Venyaminova
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p. 612 - 622
(2007/10/03)
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- Photolysis of 8-Azidoadenosine
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Irradiation of 8-azidoadenosine (I) in water, methanol or 2-mercaptoethanol at wavelenght greater than 290nm yields 8-aminoadenosine (II).
- Bose, S. N.
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