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81.
2′,3′-Bis-O-tert-butyldimethylsilyl-5′-deoxy-5′-[N-(methylcarbamoyl)amino]-N6-(N-phenylcarbamoyl)adenosine, a new member of the N6,5′-bis-ureidoadenosine class of anticancer nucleosides, is found to exhibit broad spectrum antiproliferative activity. A majority of the cell lines in the NCI-60 are inhibited with an average GI50 = 3.13 μM. Selective toxicity against human colon cancer cell lines (COLO 205, HCC-2998, HCT-116, HT29, KM12) was also exhibited (LC50’s = 6-10 μM). 相似文献
82.
Differential reactivity of alpha and beta 2'-deoxyribonucleosides towards protonation and metalation
Müller J Böhme D Düpre N Mehring M Polonius FA 《Journal of inorganic biochemistry》2007,101(3):470-476
The reactivity of artificial 2'-deoxyribonucleosides, designed as nucleoside surrogates in metal-mediated base pairs, towards protonation and metalation has been shown to be dependent on the choice of the anomer. The alpha nucleosides comprising the aglycones imidazole, 1,2,4-triazole, benzimidazole and imidazo[4,5-b]pyridine are more basic than the respective beta nucleosides as was shown by a combined experimental and theoretical approach. The DeltapK(a) values observed experimentally are in the range of 0.19+/-0.03 to 0.41+/-0.07 (with the error representing three times the standard deviation of the mean value). An independent confirmation of this differential reactivity was obtained from density functional theory (DFT) calculations using 1,2,4-triazole nucleoside as an example. The result of these calculations is in good agreement with the experimental data (DeltapK(a)=0.16 vs. 0.21+/-0.07). The stability of the respective metal ion complexes of the anomeric 1,2,4-triazole nucleosides follows the same trend as that of the respective protonated nucleosides: Those of the alpha nucleoside are more stable than those of the beta nucleoside (Deltalogbeta(2)=0.6+/-0.2 for the 2:1 complex with Ag(+); Deltalogbeta(1)=0.51+/-0.07 for the 1:1 complex with Hg(2+)). These slightly different reactivities will be useful for fine-tuning the metal-ion binding behavior of oligonucleotides containing metal-mediated base pairs. 相似文献
83.
Francesco Sgarrella Luciano Frassetto Simone Allegrini Marcella Camici Maria Caterina Carta Paolo Fadda Maria Grazia Tozzi Piero Luigi Ipata 《Biochimica et Biophysica Acta (BBA)/General Subjects》2007
Adenosine phosphorylase, a purine nucleoside phosphorylase endowed with high specificity for adenine nucleosides, was purified 117-fold from vegetative forms of Bacillus cereus. The purification procedure included ammonium sulphate fractionation, pH 4 treatment, ion exchange chromatography on DEAE-Sephacel, gel filtration on Sephacryl S-300 HR and affinity chromatography on N6-adenosyl agarose. The enzyme shows a good stability to both temperature and pH. It appears to be a homohexamer of 164 ± 5 kDa. Kinetic characterization confirmed the specificity of this phosphorylase for 6-aminopurine nucleosides. Adenosine was the preferred substrate for nucleoside phosphorolysis (kcat/Km 2.1 × 106 s− 1 M− 1), followed by 2′-deoxyadenosine (kcat/Km 4.2 × 105 s− 1 M− 1). Apparently, the low specificity of adenosine phosphorylase towards 6-oxopurine nucleosides is due to a slow catalytic rate rather than to poor substrate binding. 相似文献
84.
Jonathan Somme Bart Van Laer Martine Roovers Jan Steyaert Wim Versées Louis Droogmans 《RNA (New York, N.Y.)》2014,20(8):1257-1271
The 2′-O-methylation of the nucleoside at position 32 of tRNA is found in organisms belonging to the three domains of life. Unrelated enzymes catalyzing this modification in Bacteria (TrmJ) and Eukarya (Trm7) have already been identified, but until now, no information is available for the archaeal enzyme. In this work we have identified the methyltransferase of the archaeon Sulfolobus acidocaldarius responsible for the 2′-O-methylation at position 32. This enzyme is a homolog of the bacterial TrmJ. Remarkably, both enzymes have different specificities for the nature of the nucleoside at position 32. While the four canonical nucleosides are substrates of the Escherichia coli enzyme, the archaeal TrmJ can only methylate the ribose of a cytidine. Moreover, the two enzymes recognize their tRNA substrates in a different way. We have solved the crystal structure of the catalytic domain of both enzymes to gain better understanding of these differences at a molecular level. 相似文献
85.
Pawel Romaszko Ewa M. Slominska Ryszard T. Smolenski 《Nucleosides, nucleotides & nucleic acids》2014,33(4-6):333-337
We recently described a new nicotinamide derivative: 4-pyridone-3-carboxamide ribonucleoside (4PYR) and its conversion to intracellular metabolites (4PYR monophosphate: 4PYMP and 4PYR adenylate diphosphate: 4PYRAD). The aim of this study was to clarify the metabolism and physiological effects of brief exposure to 4PYR in perfused rat heart. Rat hearts were perfused in Langendorff mode. After 15 min equilibration, 100 μM 4PYR (or solvent in controls) was infused into coronary circulation for 5 min. Coronary flow was recorded with electromagnetic flow meter and left ventricular mechanical function was assessed with intraventricular baloon by constructing pressure–volume relations. After perfusion hearts were freeze-clamped and analyzed using HPLC for phosphocreatine, creatine, ATP with metabolites as well as 4PYR metabolites. 4PYR infused into the coronary circulation was rapidly converted in the heart into 4PYMP and 4PYRAD with concentrations reaching 85.6 ± 46.9 and 43.9 ± 6.4 nmol/g dry weight, respectively, while control concentrations were below 20 nmol/g. 4PYR had no effect on baseline coronary flow (11.9 ± 2.3 ml/min versus 11.0 ± 2.7 ml/min in control) or stimulated by shear stress (23.2 ± 4.5 ml/min versus 23.1 ± 5.2 ml/min in control). Both systolic and diastolic left ventricular mechanical function were not affected by 4PYR. No difference was noted for heart rate. Myocardial concentrations of ATP or phosphocreatine were also not affected by 4PYR. We conclude that 4PYR has no immediate effect on coronary endothelium or cardiomyocyte functions such as coronary flow, rhythm, diastolic properties, or contractility despite rapid incorporation into intracellular metabolites. This study also indicates the lack of effect on purinergic receptors. 相似文献
86.
《Bioorganic & medicinal chemistry letters》2014,24(12):2703-2706
A cyclic form of N6-threonylcarbamoyladenosine bearing an oxazolone moiety (ct6A) was discovered very recently at the position 37 in several tRNA sequences. Our study on the synthesized 5′,3′,2′-O-acetylated derivative of ct6A confirmed high stability of the modified nucleoside under physiological conditions (PBS buffer, pH 7.4) and revealed remarkable stability of the oxazolone ring in acidic (100 mM HCl, pH 1) and basic (0.1 mM NaOH, pH 10) conditions. This feature may allow for the post-synthetic conversion of t6A into ct6A in assembled oligoribonucleotides. 相似文献
87.
The medicinal chemistry and pharmacology of the four subtypes of adenosine receptors (ARs) and the eight subtypes of P2Y receptors (P2YRs, activated by a range of purine and pyrimidine mono- and dinucleotides) has recently advanced significantly leading to selective ligands. X-ray crystallographic structures of both agonist- and antagonist-bound forms of the A(2A)AR have provided unprecedented three-dimensional detail concerning molecular recognition in the binding site and the conformational changes in receptor activation. It is apparent that this ubiquitous cell signaling system has implications for understanding and treating many diseases. ATP and other nucleotides are readily released from intracellular sources under conditions of injury and organ stress, such as hypoxia, ischemia, or mechanical stress, and through channels and vesicular release. Adenosine may be generated extracellularly or by cellular release. Therefore, depending on pathophysiological factors, in a given tissue, there is often a tonic activation of one or more of the ARs or P2YRs that can be modulated by exogenous agents for a beneficial effect. Thus, this field has provided fertile ground for pharmaceutical development, leading to clinical trials of selective receptor ligands as imaging agents or for conditions including cardiac arrhythmias, ischemia/reperfusion injury, diabetes, pain, thrombosis, Parkinson's disease, rheumatoid arthritis, psoriasis, dry eye disease, pulmonary diseases such as cystic fibrosis, glaucoma, cancer, chronic hepatitis C, and other diseases. 相似文献
88.
Although vinyl sulfone-modified- (VSM) pent-2'-enofuranosyl nucleosides 2 and hex-2-enopyranosyl glycoside 4 are easily synthesized from the corresponding mesylated sulfones 1c and 3c, respectively, via an oxidation-mesylation-elimination route, the 3'-C-sulfonyl-hex-2'-enopyranosylthymine 11 is not obtained from 10 and a glycal derivative 12 is formed instead. On the other hand, 3'-C-sulfonyl-hex-3'-enopyranosylthymine 20 is easily synthesized from the mesylated sulfone 19. Again unlike the reaction patterns of VSM-pent-2'-enofuranosyl nucleosides 2 and hex-2-enopyranosyl glycosides 4 as Michael acceptors, the reactions of nucleophiles with 3'-C-sulfonyl-hex-3'-enopyranosylthymine 20 yielded a rearranged product 21 instead of Michael adducts. 相似文献
89.
Adenine, guanine, uracil and the corresponding nucleosides were identified in mature wheat grain. On germination, contents of these compounds changed in a regular pattern. Amounts of the free bases rose immediately and remained at the increased levels for a short period (3–6 hr). Nucleoside content decreased at the initial phase and increased sharply 12 to 48 hr after germination. 相似文献
90.
Yahya El-Kattan Tsu-Hsing Lin Minwan Wu V. Satish Kumar Pravin L. Kotian Ajit Ghosh 《Nucleosides, nucleotides & nucleic acids》2013,32(10-12):1597-1611
A number of N 6 -substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives having hydroxymethyl at C-1′-position were prepared from the appropriate 6-chloroadenine derivative. The syntheses of the corresponding prodrugs of these compounds are also reported. These compounds showed poor activity against HCV in replicon assay. 相似文献