1818-71-9Relevant academic research and scientific papers
Subsecond detection of physiological adenosine concentrations using fast-scan cyclic voltammetry
Swamy, B. E. Kumara,Venton, B. Jill
, p. 744 - 750 (2007)
Adenosine modulates blood flow and neurotransmission and may be protective during pathological conditions such as ischemia and stroke. A real-time sensor of adenosine concentrations is needed to understand its physiological actions and the extent of receptor activation. Microelectrodes are advantageous for in vivo measurements because they are small and can make fast measurements. The goal of this study was to characterize detection of physiological adenosine concentration changes at carbon-fiber microelectrodes with subsecond temporal resolution. The oxidation potential of adenosine is +1.3 V, so fast-scan cyclic voltammetry (FSCV) was performed with an applied potential from -0.4 to 1.5 V and back at 400 V/s every 100 ms. Two oxidation peaks were detected for adenosine with T-650 carbon fibers. The second oxidation peak at 1.0 V occurs after the initial oxidation at 1.5 V and is due to a sequential oxidation step. Adsorption was maximized to obtain detection limits of 15 nM, lower than basal adenosine concentrations in the brain. The electrode was insensitive to the metabolite inosine and seven times more sensitive to adenosine than ATP. The enzymatic degradation of adenosine was monitored with FSCV. This microelectrode sensor will be valuable for biological monitoring of adenosine.
2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5′-nucleotidase (CD73) Inhibitors with Variable Binding Modes
Bhattarai, Sanjay,Pippel, Jan,Scaletti, Emma,Idris, Riham,Freundlieb, Marianne,Rolshoven, Georg,Renn, Christian,Lee, Sang-Yong,Abdelrahman, Aliaa,Zimmermann, Herbert,El-Tayeb, Ali,Müller, Christa E.,Str?ter, Norbert
, p. 2941 - 2957 (2020/04/10)
CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.
Novel isoguanine derivative of unlocked nucleic acid—Investigations of thermodynamics and biological potential of modified thrombin binding aptamer
Kotkowiak, Weronika,Czapik, Tomasz,Pasternak, Anna
, (2018/05/30)
Thrombin binding aptamer (TBA), is a short DNA 15-mer that forms G-quadruplex structure and possesses anticoagulant properties. Some chemical modifications, including unlocked nucleic acids (UNA), 20-deoxy-isoguanosine and 20-deoxy-4-thiouridine were previously found to enhance the biological activity of TBA. In this paper, we present thermodynamic and biological characteristics of TBA variants that have been modified with novel isoguanine derivative of UNA as well as isoguanosine. Additionally, UNA-4-thiouracil and 4-thiouridine were also introduced simultaneously with isoguanine derivatives. Thermodynamic analysis indicates that the presence of isoguanosine in UNA or RNA series significantly decreases the stability of G-quadruplex structure. The highest destabilization is observed for substitution at one of the G-tetrad position. Addition of 4-thiouridine in UNA or RNA series usually decreases the unfavorable energetic cost of the presence of UNA or RNA isoguanine. Circular dichroism and thermal denaturation spectra in connection with thrombin time assay indicate that the introduction of UNA-isoguanine or isoguanosine into TBA negatively affects G-quadruplex folding and TBA anticoagulant properties. These findings demonstrate that the highly-ordered structure of TBA is essential for inhibition of thrombin activity.
High-throughput five minute microwave accelerated glycosylation approach to the synthesis of nucleoside libraries
Bookser, Brett C.,Raffaele, Nicholas B.
, p. 173 - 179 (2007/10/03)
The Vorbrueggen glycosylation reaction was adapted into a one-step 5 min/130 °C microwave assisted reaction. Triethanolamine in acetontrile containing 2% water was determined to be optimal for the neutralization of trimethylsilyl inflate allowing for direct MPLC purification of the reaction mixture. When coupled with a NH3/methanol deprotection reaction, a high-throughput method of nucleoside library synthesis was enabled. The method was demonstrated by examining the ribosylation of 48 nitrogen containing heteroaromatic bases that included 25 purines, four pyrazolopyrimidines, two 8-azapurines, one 2-azapurine, two imidazopyridines, two benzimidazoles, three imidazoles, three 1,2,4-triazoles, two pyrimidines, two 3-deazapyrimidines, one quinazolinedione, and one alloxazine. Of these, 32 yielded single regioisomer products, and six resulted in separable mixtures. Seven examples provided inseparable regioisomer mixtures of -two to three compounds (16 nucleosides), and three examples failed to yield isolable products. For the 45 single isomers isolated, the average two-step overall yield ± SD was 26 ± 16%, and the average purity ± SD was 95 ± 6%. A total of 58 different nucleosides were prepared of which 15 had not previously been accessed directly from glycosylation/deprotection of a readily available base.
Synthesis of 2'-deoxyisoguanosine 5'-triphosphate and 2'-deoxy-5 methylisocytidine 5'-triphosphate
Jurczyk, Simona C.,Kodra, Janos T.,Park, Jeong-Ho,Benner, Steven A.,Battersby, Thomas R.
, p. 1005 - 1015 (2007/10/03)
The syntheses of the 5'-triphosphates of 2'-deoxyisoguanosine (= p3isoC(d)) and 2'-deoxy-5-methylisocytidine (= p3me5isoC(d)), two new bases for the genetic alphabet, are described. The triphosphates were synthesized from the corresponding nucleosides using a transient-protection procedure. The introduction of a methyl group at the 5-position of 2'- deoxyisocytidine remarkably improved the stability of the triphosphate. Characterization of the triphosphates included enzymatic incorporation opposite the complementary base in a template oligonucleotide.
Synthesis of Oligonucleotides Containing 2′-Deoxyisoguanosine and 2′-Deoxy-5-methylisocytidine Using Phosphoramidite Chemistry
Jurczyk, Simona C.,Kodra, Janos T.,David Rozzell,Benner, Steven A.,Battersby, Thomas R.
, p. 793 - 811 (2007/10/03)
The synthesis of oligonucleotides containing 2′-deoxy-5-methylisocytidine and 2′-deoxyisoguanosine using phosphoramidite chemistry in solid-phase oligonucleotide synthesis is described. Supporting previous observations, the N,N-diisobutylformamidine moiet
Improved Synthesis of Isoguanosine and 6-Substituted Xanthosine Derivatives
Napoli, Lorenzo De,Montesarchio, Daniela,Piccialli, Gennaro,Santacroce, Ciro,Varra, Michela
, p. 15 - 18 (2007/10/02)
Isoguanosine 1 was obtained in 76percent overall yield starting from 2',3',5'-tri-O-acetylxanthosine 3 in a reaction involving the chloro derivative 4 and the N-(purin-6-yl)pyridinium salt derivative 8 which also proved to be new and valuable synthetic intermediates in the obtainment of C-6-substituted xanthosine derivatives.
The synthesis of 2-fluoropurine nucleosides
Krolikiewicz,Vorbruggen
, p. 673 - 678 (2007/10/02)
2-Aminoadenosine, obtained by silylation-amination from guanosine, is readily converted by KNO2/HF/Pyridine in up to 80% yield into 2- fluoradenosine, which is a convenient starting material for the preparation of 9(β-D-arabinofuranosyl)-2-fluoroadenine 5'-phosphate (Fludara). N6,N6- Pentamethylene-2-aminoadenosine and guanosine afford likewise the corresponding 2-fluoropurine nucleosides in high yields.
Site-specific enzymatic incorporation of an unnatural base, n6-(6-ammohexyl)isoguanosine, into RNA
Tor, Yitzhak,Dervan, Peter B.
, p. 4461 - 4467 (2007/10/02)
An efficient enzymatic method is described for the sequence-specific incorporation of a functionalizable modified base into RNA molecules. A deoxy-5-methylisocytidine (dMeisoC) in the DNA template directs the T7 RNA polymerase incorporation of
Conversion of Guanosine into Isoguanosine and Derivatives
Divakar, K. J.,Mottahedeh, Mina,Reese, Colin B.,Sanghvi, Yogesh S.,Swift, Karl A. D.
, p. 771 - 774 (2007/10/02)
Treatment of 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine 7, which is readily prepared from guanosine 2 in two steps, with toluene-4-thiol and triethylamine followed by sodium nitrite in aqueous acetic acid gives 6-(4-methylphenyl)thio
