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PubMed1997

Simultaneous determination of purine bases, ribonucleosides and ribonucleotides by capillary electrophoresis-electrochemistry with a copper electrode.

Simultaneous determination of purine bases, ribonucleosides and ribonucleotides was achieved by coupling capillary electrophoresis (CE) with wall-jet amperometric detection. A 200 microm diameter copper disk electrode was applied at working potential, +0.65 V vs. saturated calomel electrode. The current response of high sensitivity and stability was obtained in strong basic solutions which were suitable for satisfactory CE separations. The calibration curve was linear over 2-3 orders of magnitude and the limits of detection for adenine, guanine, xanthine, uric acid, adenosine, guanosine, adenosine-5'- monophosphate and guanosine-5'-monophosphate were below 9 fmol (SIN=3). The use of this method for the separation and detection of compounds present in human plasma samples was reported.

Calibration↗
PubMed1982

High-performance liquid chromatographic determination of purine and pyrimidine bases, ribonucleosides, deoxyribonucleosides and cyclic ribonucleotides in biological fluids.

A method is presented for the separation and quantitative determination of compounds normally related to purine and pyrimidine metabolism in biological material. The retention behaviour of nucleobases, ribonucleosides, deoxyribonucleosides and cyclic ribonucleotides has been systematically investigated by reversed-phase high-performance liquid chromatography using a non-linear gradient. Ultimately a separation of the purine and pyrimidine compounds was achieved in a 35-min run with an average detection limit of 5-10 pmol per injection. Recoveries of standards added to urine, plasma or serum were 96 +/- 5%.

Chromatography, High Pressure Liquid↗
PubMed1999

Properties of mixed backbone oligonucleotides containing 3'-O-methyl ribonucleosides.

Oligonucleotides containing 3'-O-methyl ribonucleosides were synthesized, and their thermal stabilities and global conformations with RNA and DNA have been studied. The duplexes displayed lower T(m) values as compared to the unmodified ones, and adopted A-conformations. Furthermore, they are not a substrate for RNase H, are slightly resistant to snake venom phosphodiesterase, and are not cleaved by nuclease S 1.

Base Sequence↗
PubMed1993

2'-C-methyladenosine and 2'-C-methyluridine 5'-diphosphates are mechanism-based inhibitors of ribonucleoside diphosphate reductase from Corynebacterium nephridii.

The interaction of the adenyosylcobalamin-dependent ribonucleoside diphosphate reductase of Cornyebacterium nephridii with 2'-C-methyladenosine 5'-diphosphate (2'-MeADP) and 2'-C-methyluridine 5'-diphosphate (2'-MeUDP) has been investigated. The nucleotide analogs are converted to adenine and uracil, respectively, suggesting that they may be mechanism-based inhibitors. In addition, both analogs generate nucleotides with properties expected for the 2'-deoxy-2'-C-methylnucleotides. The nucleoside obtained after enzymatic dephosphorylation of the product formed from 2'-MeADP has been identified as 2'-deoxy-2'-C-methyladenosine by 1H NMR and mass spectroscopies. Adenine is the major product derived from 2'-MeADP, indicating that the degradation pathway predominates. During the reaction, the carbon-cobalt bond of the coenzyme is cleaved irreversibly to yield 5'-deoxyadenosine and cob(II)alamin. 2'-MeADP is a potent competitive inhibitor of the reduction of the purine nucleotides ADP and GDP, while 2'-MeUDP competitively inhibits the reduction of the pyrimidine nucleotides UDP and CDP. 2'-MeADP is a very effective promoter of the tritium exchange reaction between [5'-3H2]adenosylcobalamin and the solvent, indicating that the exchange reaction is an integral part of the overall reduction. All these observations are consistent with the reaction mechanism proposed by Stubbe and co-workers [Harris, G., Ashley, G. W., Robins, M. J., Tolman, R. L., & Stubbe, J. (1987) Biochemistry 26, 1895-1902 (1987); Stubbe, J. (1990) J. Biol. Chem. 265, 5329-5332] in which they suggest that the partitioning between reduction and inactivation occurs at the level of the 2'-deoxy-3'-ketoribonucleotide intermediate.

Adenosine Diphosphate↗
PubMed1987

Products of the inactivation of ribonucleoside diphosphate reductase from Escherichia coli with 2'-azido-2'-deoxyuridine 5'-diphosphate.

Ribonucleoside diphosphate reductase (RDPR) from Escherichia coli was completely inactivated by 1 equiv of the mechanism-based inhibitor 2'-azido-2'-deoxyuridine 5'-diphosphate (N3UDP). Incubation of RDPR with [3'-3H]N3UDP resulted in 0.2 mol of 3H released to solvent per mole of enzyme inactivated, indicating that cleavage of the 3' carbon-hydrogen bond occurred in the reaction. Incubation of RDPR with [beta-32P]N3UDP resulted in stoichiometric production of inorganic pyrophosphate. One equivalent of uracil was eliminated from N3UDP, but no azide release was detected. Analysis of the reaction of RDPR with [15N3]N3UDP by mass spectrometry revealed that the azide moiety was converted to 0.9 mol of nitrogen gas per mole of enzyme inactivated. The tyrosyl radical of the B2 subunit was destroyed during the inactivation by N3UDP as reported previously [Sjöberg, B.-M., Gräslund, A., & Eckstein, F. (1983) J. Biol. Chem. 258, 8060-8067], while the specific activity of the B1 subunit was reduced by half. Incubation of [5'-3H]N3UDP with RDPR resulted in stoichiometric covalent radiolabeling of the enzyme. Separation of the enzyme's subunits by chromatofocusing revealed that the modification was specific for the B1 subunit.

Affinity Labels↗
PubMed2000

Formation of the cystine between cysteine 225 and cysteine 462 from ribonucleoside diphosphate reductase is kinetically competent.

Participation of the formation of the cystine between cysteine 225 and cysteine 462 in the R1 protein to the enzymatic mechanism of aerobic ribonucleoside diphosphate reductase from Escherichia coli has been examined by use of rapid quenching and site-directed immunochemistry. Prereduced ribonucleotide reductase in the presence of ATP was mixed with CDP in a quench flow apparatus. The reaction was terminated with a solution of acetic acid and N-ethylmaleimide. The protein was precipitated and digested with chymotrypsin and the proteinase from Staphylococcus aureus strain V8 in the presence of N-ethylmaleimide to yield the peptide SS[S-(N-ethylsuccinimid-2-yl)cysteinyl]VLIE containing cysteine 225 and the mixed disulfide between the peptide SSCVLIE and the peptide IALCTL containing cysteine 462. These two peptides were retrieved together from the digest by immunoadsorption. The affinity-purified peptides were modified at their amino termini with the fluorescent reagent 6-aminoquinolyl-N-hydroxysuccimidyl carbamate and submitted to high-pressure liquid chromatography. The areas of the respective peaks of fluorescence corresponding to the S-(N-ethylsuccimidyl) peptide, and the mixed disulfide were used to determine the percentage of the cystine that had formed during each interval. The rate constant for the formation of the cystine following the association of free, fully reduced ribonucleotide reductase with the reactant CDP was 8 s(-)(1). Because only 50% of the active sites participated in this pre-steady-state reaction, the maximum steady-state rate consistent with the involvement of this cystine in the enzymatic reaction would be 4 s(-1). Since the turnover number of the enzyme under the same conditions in a steady state assay was only 1 s(-)(1), the formation of the cystine between these two cysteines is kinetically competent.

Adenosine Triphosphate↗
PubMed1994

Sulfinosine congeners: synthesis and antitumor activity in mice of certain N9-alkylpurines and purine ribonucleosides.

A number of N9-alkyl-substituted purines and purine ribonucleosides have been synthesized as congeners of sulfinosine and evaluated for their antileukemic activity in mice. NaH-mediated alkylation of 6-chloropurine (4) and 2-amino-6-chloropurine (5) with certain alkyl bromides gave N7- and N9-alkylated derivatives (7a-d and 6a-d), the N9-isomer being the major product. Treatment of 6a-d and 7a-d with thiourea furnished the corresponding 6-thio derivatives (9a-d and 8a-d). Amination of 9a-e with aqueous chloramine solution afforded the corresponding purine-6-sulfenamides (10-a-e), which on controlled oxidation with 3-chloroperoxbenzoic acid (MCPBA) gave the respective (R,S)-9-alkylpurine-6-sulfinamides (11a-e). A similar oxidation of 2-amino-6-(methyl/benzylthio)-9-beta-D-ribofuranosylpurine (12a and 12b) and 2-amino-9-(2-deoxy-beta-D-erythro-pentofuranosyl)-6- (methylthio)-purine (12c) with MCPBA gave the corresponding sulfoxides (13a-c), which on further oxidation furnished the respective sulfones (14a-c). Of the 20 compounds evaluated, six exhibited biologically significant anti-L1210 activity in BD2F1 mice and reduced body burdens of viable L1210 cells more than 90-97% by single treatment. Although compounds 9b and 9c at 44 mg and 40 mg/kg per day x 1 showed a T/C of 147 and 149, respectively, this group of compounds was found to be less effective than some of the sulfur-containing drugs that we previously described (e.g. sulfenosine and sulfinosine).

Animals↗
PubMed1989

Analysis of the in vitro antiviral activity of certain ribonucleosides against parainfluenza virus using a novel computer aided receptor modeling procedure.

The in vitro antiviral activity of 28 nucleosides against the parainfluenza virus type 3 has been analyzed by using a novel computer aided receptor modeling procedure. The method involves an extensive modification of our earlier work (Ghose, A. K.; Crippen, G. M. J. Med. Chem. 1985, 28, 333). It presents a more straightforward algorithm for the steps that suffered from subjectivity in the earlier method. The method first determines the possible low-energy conformations of the nucleosides, and assigns a priority value for each conformation of each molecule. It then performs the following steps repeatedly, until it finds an acceptable solution. Starting from the conformation of highest priority, the various energetically allowed conformations of the other molecules are superimposed on it. On the basis of the physicochemical property matching (or overlapping), the best superposition is determined. The superimposed molecules are dissected into a minimum number of parts and the local physicochemical properties at different regions are correlated with their binding data (antiviral activity). A modified version of distance geometry has been used for geometric comparison of the structure of the molecules. On the basis of the virus rating (VR) of 28 ribonucleosides, this procedure hypothesized the minimum-energy conformation of 6-(methylthio)-9-beta-D-ribofuranosylpurine as a reference conformation and used three physicochemical properties, namely hydrophobicity, molar refractivity, and formal charge density for property matching. The binding-site cavity was divided into seven regions or pockets to differentiate the nature of interaction quantitatively. The model suggests that the 2- and 3-positions of the purine ring and the corresponding atoms of the other rings get some steric repulsion, and nucleosides having a single five-membered heterocyclic ring will better fit this virus. The methylthio group gets a strong attraction from dispersive interaction. Both hydrophilic and dispersive groups are attractive here. Although our calculation supports the previously suggested active conformation of ribavirin, it shows that it is not the global minimum-energy conformation. The difference lies in the orientation of the amide group. The calculated viral rating from this model showed a correlation coefficient of 0.971 with the observed values, and the explained variance and the standard deviation of the fit were 0.880 and 0.125, respectively.

Antiviral Agents↗
PubMed1976

Synthesis of tetrazole ribonucleosides and their evaluation as antiviral agents.

Synthesis of 1-beta-D-ribofuranosyltetrazole and two 5-substituted derivatives, i.e., the 5-carboxamide and 5-acetamide, is described. The stereochemical structure of the parent tetrazole ribonucleoside has been established by means of nuclear Overhauser effect and x-ray crystallography. By analogy to the parent compound, the two 5-substituted tetrazole nucleosides are also assigned the beta configuration on the basis of the NMR coupling constant of the anomeric proton and the site of N-ribosylation is determined by 13C NMR studies. Results are also presented on antiviral testing of these synthetic tetrazole nucleosides against influenza A2/Asian/J-305 virus infection in mice.

Animals↗
PubMed1984

Mesoionic pyridazine ribonucleosides. A novel biologically active nucleoside metabolite.

4-Cyano-3-oxido-1-beta-D-ribofuranosylpyridazinium (10a) has been prepared from 4-cyano-3(2H)-pyridazinone (4) by using a low-temperature, kinetically controlled, silyl Hilbert-Johnson reaction followed by deblocking of the resulting triacetate derivative, 8a, with NaHCO3 in methanol. 10a is apparently the first example of a mesoionic analogue of a pyrimidine nucleoside. It was discovered as a urine metabolite of 4-cyano-3(2H)-pyridazinone (4) in mice. 10a possesses Gram-negative antibacterial activity in vivo against a systemic Escherichia coli infection in mice with an ED50 of 25-50 mg/kg. A series of 4-substituted 3-oxidopyridazinium ribonucleosides, 11a-h, were synthesized as analogues of 10a. 4-Chloro-3-oxido-1-beta-D-ribofuranosylpyridazinium (11a) was found to be several times more active than 10a against E. coli in vitro although it showed no in vivo activity.

Animals↗
PubMed1996

Synthesis and antiviral evaluation of certain disubstituted benzimidazole ribonucleosides.

Ribosylation of 2-chloro-5(6)-nitrobenzimidazole (3) gave 2-chloro-5-nitro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)benzimidazol e (4a) and 2-chloro-6-nitro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)benzimidazol e (4b) as a mixture of positional isomers. Subsequent hydrogenation of this mixture over Raney Nickel afforded the corresponding 5-amino and 6-amino derivatives 5 and 6. At this stage the products were readily resolved via silica column chromatography into pure isomeric forms, and the pure isomers 5 and 6 were diazotized with tert-butyl nitrite and cupric chloride to furnish the isomerically pure 5-chloro derivative 2a and 6-chloro derivative 2b. Deprotection of 5, 6, 2a, and 2b with methanolic ammonia yielded the free nucleosides 5-amino-2-chloro-1-(beta-D-ribofuranosyl)benzimidazole (7), 6-amino-2-chloro-1-(beta-D-ribofuranosyl)-benzimidazole (8), 2,5-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (9), and 2,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (10), respectively. Treatment of 10 with thiourea afforded 6-chloro-1-(beta-D-ribofuranosyl)benzimidazole-2-thione (14). Alkylation of 14 with methyl iodide and benzyl bromide gave good yields of the corresponding 2-methylthio (12) and the 2-benzylthio (13) analogs. The synthesis of 6-chloro-2-methoxy-1-(beta-D-ribofuranosyl)benzimidazole (11) was accomplished by the treatment of 2b with sodium methoxide in methanol. A difference NOE spectroscopic experiment was conducted to allow unequivocal assignment of regiochemistry to the positional isomers 5 and 6. Evaluation of compounds for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 revealed that the heterocycle 3 was active against both viruses but also was cytotoxic. Only the dichloro compounds 9 and 10 were weakly active against HCMV and noncytotoxic in their antiviral dose range. These data further substantiate the conclusion that activity against HCMV at noncytotoxic concentrations by benzimidazole ribonucleosides requires a halogen not only at the 2-position, but also more than one halogen on the benzene moiety.

Antiviral Agents↗
PubMed1999

Domain-structured N1,N2-derivatized hydrazines as inhibitors of ribonucleoside diphosphate reductase: redox-cycling considerations.

Eight analogues of 1-[5-halogenosalicylidene]-2-[2'-pyridinoyl]hydrazine and -[2'-pyridyl]hydrazine, four of 1-[pyridoxylidene]-2-[2'-pyridinoyl]hydrazine, seven of 1-[pyridoxylidene]-2-[2'-pyridyl]hydrazine, and one each of 1, 2-bis[pyridoxylidene]diaminoethane and bis[pyridoxylidenehydrazino]phthalazine were synthesized. Their solutions in DMF were assayed for activity against the metalloenzyme ribonucleoside diphosphate reductase (RdR), prepared from a subcutaneously growing murine tumor (sarcoma 180) implanted in B6D2F3 male mice. The 14C-labeled CDP reductase was assayed by the modified method of Takeda and Weber, in which [14C]cytidine was separated from deoxycytidine by thin-layer chromatography (TLC) on cellulose foil. Distribution of radioactivity was assessed with an automatic TLC linear analyzer. Of the 31 compounds tested, 13 were essentially inactive, 7 were highly active against RdR, and the remaining 20 were slightly more active than hydroxyurea (used as a reference compound). The mechanism of inhibition is discussed in terms of three alternative pathways, initiated by sequestration of iron embedded in the R1 subunit of the metalloenzyme to form a C-centered chelate radical (via redox cycling). Alternatively, the latter could either reduce the tyrosyl radical or intercept radicals generated in the reduction process.

Animals↗
PubMed2000

Design, synthesis, and biological evaluation of tricyclic nucleosides (dimensional probes) as analogues of certain antiviral polyhalogenated benzimidazole ribonucleosides.

The polyhalogenated benzimidazole nucleosides 2,5, 6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) and the 2-bromo analogue (BDCRB) were synthesized in our laboratory and established as potent and selective inhibitors of human cytomegalovirus (HCMV) with a novel mode of action. In an effort to study the behavior of the key substructure in a dimensionally extended manner and probe the spatial limitation of the target enzyme(s), a series of 2-substituted 6, 7-dichloro-1-(beta-D-ribofuranosyl)naphtho¿2,3-dĭmidazoles and the N1- and N3-ribonucleosides of 2-substituted 6,7-dichloroimidazo¿4, 5-bquinolines were prepared. The nucleosides 6, 7-dichloro-1-(beta-D-ribofuranosyl)imidazo¿4,5-bquinolin-2-one and 6,7-dichloro-3-(beta-D-ribofuranosyl)imidazo¿4,5-bquinolin-2-one were selected and used as the key synthetic intermediates in the imidazo¿4,5-bquinoline series. Evaluation of the compounds for activity against HCMV and herpes simplex virus type 1 revealed that the trichloro analogues of TCRB (2a, 3a) were nearly as active against HCMV as TCRB but were more cytotoxic. The results suggest that extending the heterocycle of TCRB affected the affinity for the HCMV target only slightly but increased the affinity for cellular enzymes.

Antiviral Agents↗
PubMed2001

Total synthesis of 2',3',4',5',5' '-(2)h(5)-ribonucleosides: the key building blocks for NMR structure elucidation of large RNA.

The diastereospecific chemical syntheses of uridine-2',3',4',5',5' '-(2)H(5) (21a), adenosine-2',3',4',5',5' '-(2)H(5) (21b), cytidine-2',3',4',5',5' '-(2)H(5)(2)H(5) (21c), and guanosine-2',3',4',5',5' '-(2)H(5) (21d) (>97 atom % (2)H at C2', C3', C4', and C5'/C5' ') have been achieved for their use in the solution NMR structure determination of oligo-RNA by the Uppsala "NMR-window" concept (refs 4a-c, 5a, 6), in which a small (1)H segment is NMR-visible, while the rest is made NMR-invisible by incorporation of the deuterated blocks 21a-d. The deuterated ribonucleosides 21a-d have been prepared by the condensation of appropriately protected aglycone with 1-O-acetyl-2,3,5-tri-O-(4-toluoyl)-alpha/beta-D-ribofuranose-2,3,4,5,5'-(2)H(5) (19), which has been obtained via diastereospecific deuterium incorporation at the C2 center of appropriate D-ribose-(2)H(4) derivatives either through an oxidation-reduction-inversion sequence or a one-step deuterium-proton exchange in high overall yield (44% and 24%, respectively).

Deuterium↗
PubMed2005

Stereoselective synthesis of beta-anomeric 4'-thiaspirocyclic ribonucleosides carrying the full complement of RNA-level hydroxyl substitution.

[reaction: see text] Stereoselective syntheses of a group of 4'-thiaspirocyclic ribonucleosides featuring both pyrimidine and purine classes and both possible configurations at C-5' are described. Use is made of the Pummerer reaction of substrates carrying an alpha-oriented 2,4-dimethoxybenzoyloxy substituent at C-2 in order to gain reliable stereocontrol via neighboring group participation. Irrespective of the S or R configuration of the pivotal sulfoxide intermediates, the nucleobase is captured from the beta-face. The competing process is formation of unsaturated sulfoxides, presumably via competing E2-type elimination. Although differences in reactivity between the two stereoisomeric series were noted, the common route has successfully given rise for the first time to desirable beta-anomeric sulfur-containing spiroribonucleosides with minimum formation of the alpha-anomers.

Cyclization↗
PubMed2005

Chemically stabilized phenylboranylidene groups having a dimethoxytrityl group as a colorimetrically detectable protecting group designed for cis-1,2-diol functions of ribonucleosides in the solid-phase synthesis of m2(2,2)G5'ppT.

To not only improve the inherently poor stability of the phenylboranylidene group as a protecting group of the 2',3'-cis-diol function of ribonucleosides but also introduce a colorimetrically detectable function into its mother structure, various 2-[(dialkylamino)methyl]phenylboronic acid derivatives having a [(4,4'-dimethoxytrityl)oxy]methyl group were synthesized. The reaction of uridine with these substituted phenylboronic acid derivatives gave the corresponding 2',3'-O-phenylboranylideneuridine derivatives. The stability of these phenylboranylidene groups was examined. As a result, it was shown that the steric hindrance around the amino group greatly influenced the stability of the 2-substituted phenylboranylidene groups. The 2-aminomethyl-5-[[(4,4'-dimethoxytrityl)oxy]methyl]phenylboranylidene group was the most stable. Its 2-dimethylamino counterpart, the 2-[(dimethylamino)methyl]-5-[[(4,4'-dimethoxytrityl)oxy]methyl]phenylboranylidene group, was the second most stable. When the most and second stable protecting groups were applied to the synthesis of m(2)(2,2)G(5)(')ppT on controlled pore glass, the second stable protecting group showed the best result. The use of this DMTr-containing protecting group enabled us to estimate colorimetrically the amount of the m(2)(2,2)G residue that was incorporated into the reactive site of the pT-loaded CPG resin.

Boron Compounds↗
PubMed1996

Boronic acids facilitate the transport of ribonucleosides through lipid bilayers.

Boronic acids were found to facilitate the transport of various ribonucleosides in and out of liposomes (artificial cells). Most experiments were conducted with large unilamellar vesicles composed of dipalmitoylphosphatidyl choline, cholesterol, and phosphatidic acid in the ratio 20:15:2. Rates of nucleoside efflux were determined by a UV assay, whereas the influx experiments used a radiotracer method. Five boronic acids were studied: 3,5-bis(trifluoromethyl)phenylboronic acid (1), 3,5-dichlorophenylboronic acid (2), 4-tert-butylphenylboronic acid (3), 1-butylboronic acid (4), and 4-carboxyphenylboronic acid (5). The order of carrier effectiveness was found to be 1 > 3 > 2 >> 4 >> 5. Efflux and influx experiments with mixtures of nucleosides and sucrose showed virtually complete transport selectivity in favor of the nucleosides. Mechanistic studies indicate that the nucleoside transport mechanism involves transient formation of a lipophilic, trigonal boronate ester.

Boronic Acids↗
PubMed2001

Synthesis and analysis of RNA containing 6-trifluoromethylpurine ribonucleoside.

We report the synthesis of a 5'-DMT-2'-TBDMS-protected phosphoramidite of 6-trifluoromethylpurine ribonucleoside ((TFM)P) and its use in the site-specific incorporation of 6-trifluoromethylpurine into RNA. Properties of (TFM)P-substituted RNA suggest it will be valuable in the study of RNA structure and the binding of RNA-modifying enzymes, particularly the RNA-editing adenosine deaminases. Reaction: see text.

Amides↗