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PubMed1976

Active site of ribonucleoside diphosphate reductase from Escherichia coli. Inactivation of the enzyme by 2'-substituted ribonucleoside diphosphates.

Ribonucleoside diphosphate reductase is an allosteric enzyme consisting of two nonidentical subunits, proteins B1 and B2. B1 contains dithiols which participate in the oxidation-reduction reactions of electron transport, while B2 contains a free radical essential for activity. Ribonucleoside diphosphates are bound to B1 but not to B2. Addition of 2'-deoxy-2'-chloro ribonucleoside diphosphates to ribonucleotide reductase irreversibly inactivates B1 without affecting B2. The reaction is specific since (a) it requires the presence of active B2, (b) it is controlled by allosteric effectors, (c) B1 is protected against inactivation by the normal substrates, and (d) the chloro-substituted nucleoside monophosphates have no effect. The inactivation of B1 is caused by a modification of the oxidation-reduction dithiols. The chloro derivatives decompose into free base, chloride ion, and 2-deoxyribose 5-diphosphate as a consequence of reaction with the enzyme. 2'-Deoxy-2"-azido ribonucleoside diphosphates cause an irreversible inactivation of B2 without affecting B1. The reaction is specific by the above criteria, indicating that the azido derivatives also bind to the active site of the enzyme. On reduction by ribonucleotide reductase, the azido derivatives function as radical scavengers and selectively destroy the free radical of B2, indicating that this radical participates in ribonucleotide reduction directly. On the basis of these results, a model of the active site of ribonucleotide reductase is proposed in which the site is formed from both B1 and B2. In the site the electron-donating oxidation-reduction active dithiols of B1 are in close contact with the free radical of B2. The azido derivative also inactivates the adenosylcobalamin-dependent ribonucleoside triphosphate reductase from Lactobacillus leichmannii and a ribonucleotide reductase preparation from calf thymus, indicating a general involvement of free radical intermediates in enzyme-catalyzed ribonucleotide reduction.

Escherichia coli↗

PubMed1985

Anti-leishmanial effect of allopurinol ribonucleoside and the related compounds, allopurinol, thiopurinol, thiopurinol ribonucleoside, and of formycin B, sinefungin and the lepidine WR6026.

Allopurinol and allopurinol ribonucleoside tested in vitro and in vivo for activity against Leishmania donovani. Activity in vitro was low against the amastigote form of this parasite with ED50 values of the order of 54 and 96 microM and 86 and 213 microM respectively for the two compounds. In vivo inhibition of up to 47% was achieved with allopurinol ribonucleoside given in the drinking water. However, low blood levels were found in the mouse relative to those in man. Low in vivo activity was also seen with allopurinol ribonucleoside against L. major and other species of Leishmania causing cutaneous lesions. The metabolism of allopurinol ribonucleoside in aldehyde oxidase deficient mice (inbred strains DBA/1, DBA/2) resembled that of man, but the antileishmanial activity remained low. Other compounds, formycin B, sinefungin and the lepidine WR6026 were highly active against mice infected with L. donovani or L. major.

Adenosine↗

PubMed1989

Transition-state stabilization by adenosine deaminase: 1,6-addition of water to purine ribonucleoside, the enzyme's affinity for 6-hydroxy-1,6-dihydropurine ribonucleoside, and the effective concentration of substrate water at the active site.

Positions of equilibria of highly unfavorable addition reactions, whose products are present at concentrations below the limits of detection, can be determined from equilibria of combination of anionic nucleophiles with quaternized enamines. Applied to the newly prepared 1-methylpurinium ribonucleoside cation, this method yields approximate equilibrium constants of 2 X 10(-9) M-1 for addition of water and 4 X 10(-5) M-1 for addition of N-acetylcysteine to neutral purine ribonucleoside, in dilute aqueous solution. Positions of 13C magnetic resonances and UV absorption maxima of the above complexes and comparison with those of adenosine deaminase complexes strongly suggest that purine ribonucleoside is bound by adenosine deaminase as the 1,6 covalent hydrate, not as a covalently bonded complex formed by addition of a thiol group at the active site. The favorable position of equilibrium of the hydration reaction on the enzyme, together with its extremely unfavorable position in free solution, indicates that the effective activity of substrate water at the active site is in the neighborhood of 10(10) M. The Ki value of the active diastereomer of 6-hydroxy-1,6-dihydropurine ribonucleoside is estimated as 1.6 X 10(-13) M, more than 8 orders of magnitude lower than the apparent dissociation constants of enzyme complexes with the substrate adenosine or the product inosine. The enzyme's remarkable affinity for this hydrated species, which is vanishingly rare in free solution, seems understandable in terms of the hydrate's close resemblance to a hydrated intermediate approaching the transition state in direct water attack on adenosine.

Adenosine Deaminase↗

PubMed2006

Cytostatic and antiviral 6-arylpurine ribonucleosides. Part 7: synthesis and evaluation of 6-substituted purine l-ribonucleosides.

A series of purine l-ribonucleosides 2a-2i bearing diverse C-substituents (alkyl, aryl, hetaryl or hydroxymethyl) in the position 6 were prepared by Pd-catalyzed cross-coupling reactions of 6-chloro-9-(2,3,5-tri-O-acetyl-beta-l-ribofuranosyl)purine with the corresponding organometallics followed by deprotection. Unlike their d-ribonucleoside enantiomers that possess strong cytostatic and anti-HCV activity, the l-ribonucleosides were inactive except for 6-benzylpurine nucleoside 2h showing moderate anti-HCV effect in replicon assay. A triphosphate of 2h did not inhibit HCV RNA polymerase.

Animals↗

PubMed2002

Synthesis of [5'-13C]ribonucleosides and 2'-deoxy[5'-13C]ribonucleosides.

The present efficient synthesis of [5'-13C]ribonucleosides and 2'-deoxy[5'-13C]ribonucleosides is characterized by the synthesis of the D-[5-13C]ribose derivative as an intermediate via the Wittig reaction of 4-aldehydo-D-erythrose dialkyl acetals with Ph3P13CH3I-BuLi to introduce the 13C label at the 5-position of a pentose. This was followed by the highly diastereoselective osmium dihydroxylation for the preparation of 2,3-di-O-benzyl-D-[5-13C]ribose dialkyl acetal and the cyclization from D-[5-13C]ribose dialkyl acetal derivatives to the alkyl D-[5-13C]ribofuranoside derivative by the use of LiBF(4). The obtained D-[5-13C]ribose derivative was converted into [5'-13C]ribonucleosides and subsequently into the corresponding 2'-deoxynucleosides.

Carbon Isotopes↗

PubMed1984

Development of a chromatographic method for the quantitative determination of minor ribonucleosides in physiological fluids. Characterization and quantitative determination of minor ribonucleosides in physiological fluids, Part I.

We describe an on-line multi-column high performance liquid chromatographic method for the selective clean-up and analysis of major and minor ribonucleosides in physiological fluids. Quantitative data obtained for the determination of some methylated ribonucleosides in human urines are compared with those obtained with the traditional off-line method. The on-line technique developed in our laboratory is distinguished from the off-line method by the following features: Sample clean-up and analysis of the target-compounds can easily be automatized, Total time of analysis, for example of urinary ribonucleosides, is decreased to 35 minutes, Laborious and error-prone evaporation and redissolution steps are avoided, Reliability of the overall analytical system can be controlled with ease, Small sample-volumes can be applied directly, Sensitive samples can be processed very rapidly under mild conditions, Results obtained with the on-line and off-line-techniques compare well.

Boronic Acids↗

PubMed1993

Reversal of 6-mercaptopurine and 6-methylmercaptopurine ribonucleoside cytotoxicity by amidoimidazole carboxamide ribonucleoside in Molt F4 human malignant T-lymphoblasts.

Cytotoxicity of 6-mercaptopurine (6MP) and 6-methylmercaptopurine ribonucleoside (Me-MPR) was studied in Molt F4 human malignant lymphoblasts. Both drugs are converted into methylthioIMP (Me-tIMP), which inhibits purine de novo synthesis. Addition of amidoimidazole carboxamide ribonucleoside (AICAR) circumvented inhibition of purine de novo synthesis, and thus partly prevented 6MP and Me-MPR cytotoxicity. Purine nucleotides, and especially adenine nucleotides, were recovered by addition of AICAR. Under these conditions, Me-tIMP formation decreased. The results of this study indicate that formation of Me-tIMP may be important for 6MP cytotoxicity in Molt F4 cells. These data suggest that depletion of adenine nucleotides is the main cause for Me-tIMP cytotoxicity.

Adenine Nucleotides↗

PubMed1995

Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine.

6-Methylmercaptopurine ribonucleoside-5'-phosphate (MeSPuRMP), the sole metabolite of 6-methylmercaptopurine ribonucleoside (MeSPuRib), is a strong inhibitor of purine de novo synthesis, inducing depletion of intracellular purine nucleotides and subsequent cell death in several tumor cell lines. In this study prevention of MeSPuRib cytotoxicity by compounds of the purine salvage pathway was studied in Molt F4 human malignant T-lymphoblasts. Adenosine, adenine and inosine were able to prevent depletion of the adenine nucleotide pool when used in combination with 0.5 microM MeSPuRib, but had virtually no effect on depletion of guanine nucleotides. Nevertheless, these three purine compounds were able to reduce the cytotoxic effects induced by MeSPuRib. Addition of guanosine to cells treated with 0.5 microM MeSPuRib normalized the guanine nucleotide pool, but adenine nucleotides remained depleted. Under these conditions, inhibition of cell growth was significantly decreased. With the combination of guanosine and 10 microM MeSPuRib, cytotoxicity was increased compared to 10 microM MeSPuRib alone, associated with a depletion of adenine nucleotides to 9% of untreated cells. Since cell growth and cell viability of Molt F4 cells are less inhibited by MeSPuRib under conditions where adenine nucleotide depletion is prevented by purine compounds (and where the other nucleotides are depleted) we conclude that depletion of adenine nucleotides is an important factor in MeSPuRib cytotoxicity.

Adenine↗

PubMed2001

2'-C-branched ribonucleosides. 2. Synthesis of 2'-C-beta-trifluoromethyl pyrimidine ribonucleosides.

[structure: see text]. The first synthesis of 2'-C-beta-trifluoromethyl pyrimidine ribonucleosides is described. 1,2,3,5-Tetra-O-benzoyl-2-C-beta-trifluoromethyl-alpha-D-ribofuranose (3) is prepared from 1,3,5-tri-O-benzoyl-alpha-D-ribofuranose (1) in three steps and converted to 3,5-di-O-benzoyl-2-C-beta-trifluoromethyl-alpha-D-1-ribofuranosyl bromide (5). The 1-bromo derivative (5) is found to be a powerful reaction intermediate for the synthesis of ribonucleosides. The reaction of silylated pyrimidines with (5) in the presence of HgO/HgBr2 affords exclusively the beta-anomers (6-8). Deprotection of (6-8) with ammonia in methanol yields the 2'-C-beta-trifluoromethyl nucleosides (9-11).

Glycosylation↗

PubMed2001

An efficient method for the preparation of 1'alpha-branched-chain sugar pyrimidine ribonucleosides from uridine: the first conversion of a natural nucleoside into 1'-substituted ribonucleosides.

The 1'alpha-phenylselenouridine derivative 13 was successfully synthesized by enolization of the 3',5'-O-TIPDS-2'-ketouridine 8, and was subjected to a radical reaction with a vinylsilyl tether--an efficient procedure for preparing 1'alpha-branched-chain sugar pyrimidine nucleosides. Successive treatment of 8 with LiHMDS and PhSeCl in THF at < -70 degrees C gave the desired 1'-phenylseleno products in 85% yield as an anomeric mixture of the 1'alpha-product 11 and the 1'beta-product 12 (11/12= 2.5:1). Highly stereoselective reduction at the 2'-carbonyl of the 1'alpha-product 11 occurred from the beta-face by using NaBH4/CeCl3 in MeOH, and subsequent introduction of a dimethylvinylsilyl tether at the 2'-hydroxyl gave the radical reaction substrate 14. The photochemical radical atom-transfer reaction of 14 by using a high-pressure mercury lamp proceeded effectively in benzene to give the exo-cyclized PhSe-transferred product 18, in which (PhSe)2 proved to be essential as an additive for radical atom-transfer cyclization reactions. Subsequent phenylseleno-group elimination of 18 gave the sugar-protected 1'alpha-vinyluridine. With this procedure, 1'alpha-vinyluridine (22) and -cytidine (25), designed to be potential antitumor agents, were successfully synthesized. This study is the first example of functionalization at the anomeric 1'-position of a nucleoside by starting from a natural nucleoside to produce a ribo-type 1'-modified nucleoside.

Cyclization↗

PubMed1972