58-63-9Relevant articles and documents
Enzymatic synthesis of novel purine nucleosides bearing a chiral benzoxazine fragment
Eletskaya, Barbara Z.,Gruzdev, Dmitry A.,Krasnov, Victor P.,Levit, Galina L.,Kostromina, Maria A.,Paramonov, Alexander S.,Kayushin, Alexei L.,Muzyka, Inessa S.,Muravyova, Tatyana I.,Esipov, Roman S.,Andronova, Valeria L.,Galegov, Georgiy A.,Charushin, Valery N.,Miroshnikov, Anatoly I.,Konstantinova, Irina D.
, p. 605 - 616 (2019)
A series of ribo- and deoxyribonucleosides bearing 2-aminopurine as a nucleobase with 7,8-difluoro- 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (conjugated directly or through an aminohexanoyl spacer) was synthesized using an enzymatic transglycosylation reaction. Nucleosides 3-6 were resistant to deamination under action of adenosine deaminase (ADA) Escherichia coli and ADA from calf intestine. The antiviral activity of the modified nucleosides was evaluated against herpes simplex virus type 1 (HSV-1, strain L2). It has been shown that at sub-toxic concentrations, nucleoside (S)-4-[2-amino-9-(β-D-ribofuranosyl)-purin-6-yl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine exhibit significant antiviral activity (SI?>?32) on the model of HSV-1 in vitro, including an acyclovir-resistant virus strain (HSV-1, strain L2/R).
Kinetic and conformational studies of adenosine deaminase upon interaction with oxazepam and lorazepam
Moosavi-Movahedi,Tehrani, H. Sepassi,Amanlou,Soltani Rad,Hakimelahi,Tsai,Ataie,Saboury,Ahmad,Khalafi-Nezhad,Poursasan,Sharifizadeh
, p. 197 - 205 (2010)
Oxazepam and lorazepam inhibit the adenosine deaminase (ADA) differently. In the case of lorazepam temperature increment causes an increase in the inhibition potency whereas higher temperature reduces the inhibitory effect of oxazepam; which proposes the overall profounder structural changes in the case of lorazepam relative to those caused by oxazepam.
3'-β-ethynyl and 2'-deoxy-3'-β-ethynyl adenosines: First 3'-β- branched-adenosines substrates of adenosine deaminase
Tritsch, Denis,Jung, Pierre M. J.,Burger, Alain,Biellmann, Jean-Francois
, p. 139 - 141 (2000)
The 3'-C-branched-adenosine and 2'-deoxyadenosine analogues 1-7 were tested as substrate of adenosine deaminase. The 9-(3'-C-ethynyl-β-D-ribo- pentofuranosyl)adenine 1 and its 2'-deoxy analogue 7 were deaminated by the enzyme while the vinyl and ethyl derivatives 2 and 3 were not. The 9-(3'-C- branched-β-D-xylo-pentofuranosyl)adenines 4-6 were deaminated by the deaminase.
Contrasting behavior of conformationally locked carbocyclic nucleosides of adenosine and cytidine as substrates for deaminases
Marquez, Victor E.,Schroeder, Gottfried K.,Ludek, Olaf R.,Siddiqui, Maqbool A.,Ezzitouni, Abdallah,Wolfenden, Richard
, p. 614 - 632 (2009)
In addition to the already known differences between adenosine deaminase (ADA) and cytidine deaminase (CDA) in terms of their tertiary structure, the sphere of Zn+2 coordination, and their reverse stereochemical preference, we present evidence that the enzymes also differ significantly in terms of the North/South conformational preferences for their substrates and the extent to which the lack of the O(4') oxygen affects the kinetics of the enzymatic deamination of carbocyclic substrates. The carbocyclic nucleoside substrates used in this study have either a flexible cyclopentane ring or a rigid bicyclo[3.1.0]hexane scaffold.
Nucleolipids of Canonical Purine ?- D -Ribo-Nucleosides: Synthesis and Cytostatic/Cytotoxic Activities Toward Human and Rat Glioblastoma Cells
Knies, Christine,Hammerbacher, Katharina,Bonaterra, Gabriel A.,Kinscherf, Ralf,Rosemeyer, Helmut
, p. 129 - 141 (2016)
We report on the synthesis of two series of canonical purine ?-d-ribonucleoside nucleolipids derived from inosine and adenosine, which have been characterized by elemental analyses, electrospray ionization mass spectrometry (ESI MS) as well as by 1H and 13CNMR, and pH-dependent UV/Vis spectroscopy. A selection of the novel nucleolipids with different lipophilic moieties were first tested on their cytotoxic effect toward human macrophages. Compounds without a significant inhibitory effect on the viability of the macrophages were tested on their cytostatic/cytotoxic effect toward human astrocytoma/oligodendroglioma GOS-3 cells as well as against the rat malignant neuroectodermal BT4Ca cell line. In order to additionally investigate the potential molecular mechanisms involved in the cytotoxic effects of the derivatives on GOS-3 or BT4Ca cells, we evaluated the induction of apoptosis and observed the particular activity of the nucleolipid ethyl 3-{4-hydroxymethyl-2-methyl-6-[6-oxo-1-(3,7,11-trimethyl-dodeca-2,6,10-trienyl)-1,6-dihydro-purin-9-yl]-tetrahydro-furo[3,4-d][1,3]dioxol-2-yl}propionate (8 c) toward both human and rat glioblastoma cell lines invitro. Nucleolipids combat cancer: We report the synthesis of two nucleolipid derivatives from inosine and adenosine with different lipophilic moieties. These have no cytotoxic effect on human macrophages based on invitro side-effect tests but have antiproliferative properties against malignant glioblastoma cell lines.
Rapid, reliable, and sensitive detection of adenosine deaminase activity by UHPLC-Q-Orbitrap HRMS and its application to inhibitory activity evaluation of traditional Chinese medicines
Qi, Shenglan,Guan, Huida,Deng, Gang,Yang, Tao,Cheng, Xuemei,Liu, Wei,Liu, Ping,Wang, Changhong
, p. 175 - 181 (2018)
Adenosine deaminase (ADA), which is a key enzyme in the metabolism of purine nucleosides, plays important roles in diverse disorders, such as tuberculosis, diabetes, liver disorders, and cancer. Determination of the activities of ADA and its isoenzymes in body fluids has received considerable attention in the diagnosis and treatment of relative diseases. Ultraviolet spectroscopy with adenosine (AD) as a substrate is a classical approach for screening potential ADA inhibitors by measuring the decrease in substrate (AD) at 265 nm or increase in the product (inosine) at 248 nm. However, AD and inosine share a very close maximum absorption wavelength, and the reaction is uncertain and is frequently interfered by the background color of matrix compounds or plant extracts. Thus, the method usually yields false positive or negative results. In this study, a novel, rapid, sensitive, and accurate ultra-high-performance liquid chromatography-Q exactive hybrid quadrupole orbitrap high-resolution accurate mass spectrometric (UHPLC-Q-Orbitrap HRMS) method was developed for determining and screening ADA inhibitors by directly determining the deamination product of AD, inosine. A proper separation was achieved for inosine and chlormequat (internal standard) within 2 min via isocratic elution (0.1% formic acid:methanol = 85:15, v/v) at a flow rate of 0.3 mL min?1 on a Waters ACQUITY HSS T3 column (2.1 mm × 100 mm, 1.8 μm) following a simple precipitation of proteins. The intra- and inter-day precisions of the developed method were below 7.17% and 8.99%, respectively. The method exhibited advantages of small total reaction volume (60 μL), short running time (2 min), high sensitivity (lowest limit of quantification of 0.02 μM for inosine), and low cost (small enzyme consumption of 0.007 unit mL?1 for ADA and substrate of 3.74 μM for AD in individual inhibition), and no matrix effects (101.64%–107.12%). Stability results showed that all analytes were stable under the investigated conditions. The developed method was successfully applied to the detection of the inhibitory activity of ADA from traditional Chinese medicines.
Determination of adenosine deaminase activity in dried blood spots by a nonradiochemical assay using reversed-phase high-performance liquid chromatography
Van Kuilenburg,Zoetekouw,Meijer,Kuijpers
, p. 461 - 465 (2010)
Adenosine deaminase (ADA) deficiency is a rare metabolic disease causing severe combined immunodeficiency (SCID). An assay to determine ADA activity in dried blood spots was developed using reversed-phase HPLC. The assay was linear with reaction times up to at least 4 hours, and protein concentrations up to at least 2.2 mg/ml. The intra-assay CV and the inter-assay CV for the complete assay was 3.5 and 8.4%, respectively. The ADA activity in a control blood spot, stored at 4°C, remained stable for at least one year. Only a slightly decreased ADA activity (35 ± 13 nmol/mg/h, n = 4) was observed in heterozygotes for a c.704G > A mutation in the ADA gene when compared to that observed in controls (41 ± 13 nmol/mg/h, n = 108). In addition, increased ADA activity as found in a rare form of congenital anemia can be assessed, as observed in a bloodspot from a patient diagnosed with Diamond Blackfan anemia (ADA activity 150 nmol/mg/h). Copyright
Synthesis of 13C-labeled 5-aminoimidazole-4-carboxamide-1-β-D-[13C5] ribofuranosyl 5′-monophosphate
Zarkin, Allison K.,Elkins, Phyllis D.,Gilbert, Amanda,Jester, Teresa L.,Seltzman, Herbert H.
, p. 820 - 825 (2018)
5-Aminoimidazole-4-carboxamide-1-β-D-[13C5] ribofuranosyl 5′-monophosphate ([13C5 ribose] AICAR-PO3H2) (6) has been synthesized from [13C5]adenosine. Incorporation of the mass-label into [13C5 ribose] AICAR-PO3H2 provides a useful standard to aid in metabolite identification and quantification in monitoring metabolic pathways. A synthetic route to the 13C-labeled compound has not been previously reported. Our method employs a hybrid enzymatic, and chemical synthesis approach that applies an enzymatic conversion from adenosine to inosine followed by a ring-cleavage of the protected inosine. A direct phosphorylation of the resulting 2′,3′-isopropylidine acadesine (5) was developed to yield the title compound in 99% purity following ion exchange chromatography.
Simultaneous detection of ATP and GTP by covalently linked fluorescent ribonucleopeptide sensors
Nakano, Shun,Fukuda, Masatora,Tamura, Tomoki,Sakaguchi, Reiko,Nakata, Eiji,Morii, Takashi
, p. 3465 - 3473 (2013)
A noncovalent RNA complex embedding an aptamer function and a fluorophore-labeled peptide affords a fluorescent ribonucleopeptide (RNP) framework for constructing fluorescent sensors. By taking an advantage of the noncovalent properties of the RNP complex, the ligand-binding and fluorescence characteristics of the fluorescent RNP can be independently tuned by taking advantage of the nature of the RNA and peptide subunits, respectively. Fluorescent sensors tailored for given measurement conditions, such as a detection wavelength and a detection concentration range for a ligand of interest can be easily identified by screening of fluorescent RNP libraries. The noncovalent configuration of a RNP becomes a disadvantage when the sensor is to be utilized at very low concentrations or when multiple sensors are applied to the same solution. Here, we report a strategy to convert a fluorescent RNP sensor in the noncovalent configuration into a covalently linked stable fluorescent RNP sensor. This covalently linked fluorescent RNP sensor enabled ligand detection at a low sensor concentration, even in cell extracts. Furthermore, application of both ATP and GTP sensors enabled simultaneous detection of ATP and GTP by monitoring each wavelength corresponding to the respective sensor. Importantly, when a fluorescein-modified ATP sensor and a pyrene-modified GTP sensor were co-incubated in the same solution, the ATP sensor responded at 535 nm only to changes in the concentration of ATP, whereas the GTP sensor detected GTP at 390 nm without any effect on the ATP sensor. Finally, simultaneous monitoring by these sensors enabled real-time measurement of adenosine deaminase enzyme reactions.
L-nucleoside analogues as potential antimalarials that selectively target Plasmodium falciparum adenosine deaminase
Brown, David M.,Netting, Andrew G.,Chun, Byoung K.,Choi, Yongseok,Chu, Chung K.,Gero, Annette M.
, p. 2521 - 2532 (1999)
The L-stereoisomer analogues of D-coformycin selectively inhibited P. falciparum adenosine deaminase (ADA) in the picomolar range (L-isocoformycin, K(i) 7 pM; L-coformycin, K(i) 250 pM). While the L-nucleoside analogues, L- adenosine, 2,6-diamino-9-(L-ribofuranosyl)purine and 4-amino- 1 -(L- ribofuranosyl)pyrazolo[3,4-d]-pyrimidine were selectively deaminated by P. falciparum ADA, L-thioinosine and L-thioguanosine were not. This is the first example of 'non-physiological' L-nucleosides that serve as either substrates or inhibitors of malarial ADA and are not utilised by mammalian ADA.
