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PubMed1990

Partition coefficients and capacity factors of some nucleoside analogues.

The AIDS epidemic has brought into focus the development of antiviral agents, of which nucleoside analogues are an important class. The single most important physico-chemical property of a chemotherapeutic agent is its hydrophobicity. This paper reports the hydrophobicity, determined as log partition coefficient (P) by the shake-flask method, of 25 nucleoside analogues. The capacity factors (k') of these analogues were also obtained by reversed-phase liquid chromatography. There is a very strong linear correlation between the log P and the log k' values of all the nucleoside analogues, indicating that hydrophobicity of nucleosides can be determined by liquid chromatography. Examination of the P data indicates that an empirical mathematical relationship exists between the partition coefficient value and the molecular structure of the nucleoside analogues. A table of constants and an equation is proposed to estimate the P of nucleoside analogues.

Antiviral Agents↗
PubMed2004

Exogenous nucleosides modulate the expression of rat liver extracellular matrix genes in single cultures of primary hepatocytes and a liver stellate cell line and in their co-culture.

BACKGROUND & AIMS: We have previously reported the antifibrotic effect of dietary nucleotides in cirrhotic rats. In this work, we used primary rat hepatocytes, a liver stellate cell line (CFSC-2G) and co-cultures of both cell types to investigate the effects of exogenous nucleosides on the gene expression of various extracellular matrix components and on markers of liver function, and to ascertain whether the effects found in vivo are due to CFSC-2G, hepatocytes, or are the consequence of cell-cell interactions. RESULTS: Nucleosides enhanced fibronectin, laminin, and alpha1(I) procollagen levels in CFSC-2G and hepatocytes, as well as collagen synthesis and secretion in CFSC-2G. In contrast, nucleosides lowered fibronectin, laminin and alpha1(I) procollagen levels, and decreased collagen synthesis in co-cultures. Matrix metalloproteinase-13 content and collagen secretion increased in co-cultures incubated with nucleosides. Albumin increased in hepatocytes and co-cultures incubated in the presence of nucleosides. CONCLUSIONS: Nucleosides modulate the production of extracellular matrix in single cultures of hepatocytes and of CFSC-2G, and in co-cultures. This effect seems to be regulated at the translational level. The opposite behavior of single cultures and co-cultures is probably due to the fact that the latter model reproduces many of the physical and functional relationships observed in vivo between hepatocytes and stellate cells.

Animals↗
PubMed1999

Polarographic properties and potential carcinogenicity of some natural nucleosides and their synthetic analogues.

The polarographic reduction and the index of potential carcinogenicity tg alpha determined polarographically in aprotic conditions and in the presence of alpha-lipoic acid of nine naturally occurring and synthetic pyrimidine and six synthetic 1,3,5-triazine (5-aza) nucleosides was compared to the reduction of eight synthetic 1,3,6-triazine (6-aza) nucleosides. Nucleosides are of interest because of their key role in the nucleic acid structure and because of the antimetabolite and cytotoxic/antileukemia properties of their synthetic analogues. It was shown that polarographic reduction of the studied compounds is achieved at gradually increased potentials in the order of 6-aza < 5-aza < pyrimidine nucleosides. On other hand, the potential carcinogenicity of studied compounds increases usually in the order of pyrimidine < 6-aza << 5-aza nucleoside. The only compounds with remarkable potential carcinogenicity identified at this study were those ones from the 5-aza (1,3,5-triazine) antimetabolite series-arabinosyl-5-azacytosine (0.275), 5-aza-cytidine (0.295) and 5-aza-uracil (0.400)-and 2,2'-anhydrouridine (0.260). The relation of the data obtained to biological activity of nucleosides included in the study is discussed.

Carcinogens↗
PubMed2000

Molecular cloning of an Atlantic salmon nucleoside diphosphate kinase cDNA and its pattern of expression during embryogenesis.

To gain insight into the process of development in Atlantic salmon (Salmo salar), we sought to identify genes that were differentially expressed at gastrulation. A polymerase chain reaction-based differential screening strategy allowed for the isolation of an Atlantic salmon nucleoside diphosphate kinase cDNA (nm23). Structural characterisation showed a high degree of homology with a large number of previously isolated nucleoside diphosphate kinases (NM23s), both prokaryote and eukaryote, though it represents the first teleost nucleoside diphosphate kinase identified. Highest similarities were found with the type 1 and type 2 NM23 isoforms of mammals. Phylogenetic analysis indicates that the duplication event that gave rise to these isoforms occurred after the splitting of tetrapods and fish, suggesting that the salmon NM23 represents a more ancestral isoform. The position of the salmon sequence on the phylogenetic tree indicates that the salmon genome is expected to have at least three copies of genes from the nm23 gene family. Northern blot analysis showed a single transcript of approximately 0.7 kb in both embryonic and adult tissues. Examination of the temporal pattern of expression of salmon nucleoside diphosphate kinase during embryonic development revealed that this gene is first expressed at the time of gastrulation. Nucleoside diphosphate kinases are thought to have a vital role in regulatory processes such as signal transduction, proliferation and differentiation. Taken together, these results suggest that nucleoside diphosphate kinases have an important role to play in early embryogenic development in vertebrates.

Amino Acid Sequence↗
PubMedDate not supplied

The effect of a nucleotide-nucleoside solution on hepatic regeneration after partial hepatectomy in rats.

After hepatectomy, purine and pyrimidine metabolism is a key process in the synthesis of DNA and RNA and maintaining cellular energy metabolism. The purpose of this study is to evaluate changes in blood purine and pyrimidine levels after partial hepatectomy and the effect of purine and pyrimidine nucleoside solution injection on hepatic regeneration under the hypothesis that the rat after partial hepatectomy requires substrates for salvage nucleotide synthesis and changes blood nucleoside and nucleobase levels. Blood levels of nucleotides, nucleosides, and nucleobase by high-performance liquid chromatography method and liver ATP level by enzymatic analysis, and the effect of preoperative injection of nucleoside solution (OG-VI) on hepatic regeneration ratio and hepatocytes DNA synthesis, were assessed in rats after 70% partial hepatectomy. Decreased liver adenosine triphosphate and increased plasma xanthine and hypoxanthine after partial hepatectomy indicated an increase in catabolism of purine nucleotides in regenerating liver. Plasma thymidine and cytidine levels increased, then returned to the prevalue, suggesting that the thymidine and cytidine pool was enlarged. OG-VI increased labeling indices of hepatocytes at postoperative d 1 (POD) and hepatic regeneration ratio at POD 14. Blood purine nucleobase and pyrimidine nucleoside levels change after partial hepatectomy and preoperative supply of nucleoside solution is effective for increasing hepatocytes DNA synthesis and hepatic regeneration after partial hepatectomy.

Adenosine Triphosphate↗
PubMed2001

An approach to metal-assisted DNA base pairing: novel beta-C-nucleosides with a 2-aminophenol or a catechol as the nucleobase.

The metal-chelating beta-C-nucleoside having a phenylenediamine moiety as the nucleobase was previously found to form a stable 2:1 complex with a Pd(2+) ion in aqueous media, where hydrogen bonding is replaced by metal coordination in the base pairing, thereby creating a novel hybridization motif in duplex DNA. In this regard, we have further designed two types of artificial beta-C-nucleosides possessing a metal-chelating site (a 2-aminophenol or a catechol) as the nucleobase moiety. These artificial nucleosides are directed toward controlling the net charges of the metal-assisted base pairs. This paper describes convenient syntheses of the artificial nucleosides bearing a 2-aminophenol or a catechol moiety. Each nucleoside was directly synthesized through 2'-deoxy derivative via a Friedel-Crafts coupling reaction as the key step between the aromatic ring and ribose moiety, whereas the nucleoside having a phenylenediamine moiety was prepared in rather longer steps through an RNA type intermediate followed by the removal of 2'-hydroxyl group.

Aminophenols↗
PubMed2003

Synthesis of 2-amino-2-deoxy-beta-glycosyl-(1-->5)-nucleosides and the interaction with RNA.

1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranose and 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-beta-D-galactopyranose reacted with protected nucleosides in the presence of BF(3) as promoter at room temperature to give selectively 2-amino-2-deoxy-beta-glycosyl (1-->5)nucleosides in good yields. CD spectra and thermal melting studies showed that 2-amino-2-deoxy-beta-D-glucopyranosyl-(1-->5)-nucleosides could interact with RNA in solution and 2-deoxy-2-amino-beta-D-galactopyranosyl-(1-->5)-nucleosides (17-19) exhibit higher affinity to RNA than 2-deoxy-2-amino-beta-D-glucopyranosyl-(1-->5)-nucleosides (14-16). It indicated that the majority of interactions are established between the polar group of glycosylnucleosides and the sugar-phosphate backbone of RNA helices and weak stacking interaction is observed. The different configuration of hydroxyl group on the glycosyl moiety may affect the glycosyl-nucleoside binding to RNA by induced fit.

Aminoglycosides↗
PubMedDate not supplied

2'-modified nucleosides for site-specific labeling of oligonucleotides.

We report the synthesis of 2'-modified nucleosides designed specifically for incorporating labels into oligonucleotides. Conversion of these nucleosides to phosphoramidite and solid support-bound derivatives proceeds in good yield. Large-scale synthesis of 11-mer oligonucleotides possessing the 2'-modified nucleosides is achieved using these derivatives. Thermal denaturation studies indicate that the presence of 2'-modified nucleosides in 11-mer duplexes has minimal destabilizing effects on the duplex structure when the nucleosides are placed at the duplex termini. The powerful combination of phosphoramidite and support-bound derivatives of 2'-modified nucleosides affords the large-scale preparation of an entirely new class of oligonucleotides. The ability to synthesize oligonucleotides containing label attachment sites at 3', intervening, and 5' locations of a duplex is a significant advance in the development of oligonucleotide conjugates.

Affinity Labels↗
PubMed1989

The missing nucleoside experiment: a new technique to study recognition of DNA by protein.

We report a new technique for quickly determining which nucleosides in a DNA molecule are contacted by a sequence-specific DNA-binding protein. Our method is related to the recently reported "missing contact" experiment [Brunelle, A., & Schleif, R. F. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 6673-6679]. We treat the DNA molecule with the hydroxyl radical to randomly remove nucleosides. The ability of protein to bind to gapped DNA is assayed by gel mobility shift. Nucleosides important to protein binding are identified by sequencing gel electrophoresis. The missing nucleoside experiment can be used to scan a DNA molecule at single-nucleotide resolution in one experiment. The bacteriophage lambda repressor-OR1 and cro-OR1 complexes were analyzed to evaluate the method. For both proteins, the most important contacts are located in the protein monomer that binds to the consensus half of the operator. These contacts correspond well to those found by mutational studies, and in the cocrystal structure of the lambda repressor-operator. The missing nucleoside data show that the amino-terminal arms of lambda repressor make energetically important contacts with positions 7 and 8 and the central dyad base pair of the operator. The amino-terminal arm that makes the most extensive contacts to DNA appears to be the one that emanates from the repressor monomer that binds to the consensus half of the operator, in agreement with the cocrystal structure. The lambda cro protein does not have an amino-terminal arm, and the missing nucleoside experiment clearly shows a lack of contacts to DNA in the central region of the operator in this complex.

Base Sequence↗
PubMed2003

New base pairing motifs. The synthesis and thermal stability of oligodeoxynucleotides containing imidazopyridopyrimidine nucleosides with the ability to form four hydrogen bonds.

The synthesis and thermal stability of oligodeoxynucleotides (ODNs) containing imidazo[5',4':4,5]pyrido[2,3-d]pyrimidine nucleosides 1-4 (N(N), O(O), N(O), and O(N), respectively) with the aim of developing two sets of new base pairing motifs consisting of four hydrogen bonds (H-bonds) is described. The proposed four tricyclic nucleosides 1-4 were synthesized through the Stille coupling reaction of a 5-iodoimidazole nucleoside with an appropriate 5-stannylpyrimidine derivative, followed by an intramolecular cyclization. These nucleosides were incorporated into ODNs to investigate the H-bonding ability. When one molecule of the tricyclic nucleosides was incorporated into the center of each ODN (ODN I and II, each 17mer), no apparent specificity of base pairing was observed, and all duplexes were less stable than the duplexes containing natural G:C and A:T pairs. On the other hand, when three molecules of the tricyclic nucleosides were consecutively incorporated into the center of each ODN (ODN III and IV, each 17mer), thermal and thermodynamic stabilization of the duplexes due to the specific base pairings was observed. The melting temperature (T(m)) of the duplex containing the N(O):O(N) pairs showed the highest T(m) of 84.0 degrees C, which was 18.2 and 23.5 degrees C higher than that of the duplexes containing G:C and A:T pairs, respectively. This result implies that N(O)and O(N) form base pairs with four H-bonds when they are incorporated into ODNs. The duplex containing N(O):O(N) pairs was markedly stabilized by the assistance of the stacking ability of the imidazopyridopyrimidine bases. Thus, we developed a thermally stable new base pairing motif, which should be useful for the stabilization and regulation of a variety of DNA structures.

Base Pairing↗
PubMed1990

Synthesis and antiviral activity of 3'-deoxy-3'-C-hydroxymethyl nucleosides.

A series of 3'-branched-chain sugar nucleosides, in particular 3'-deoxy-3'-C-hydroxmethyl nucleosides, have been synthesized and evaluated as antiviral agents. Reaction of 1-(2,3-epoxy-5-O-trityl-beta-D-lyxo-pentofuranosyl) derivatives 12 and 13, of uracil and thymine, respectively, with 5,6-dihydro-2-lithio-5-methyl-1,3,5-dithiazine 14 afforded the corresponding 3'-functionalized nucleosides 15 and 16, respectively. Replacement of the trityl group with tertbutyldiphenylsilyl allowed high yielding hydrolysis of the 3'-function to give the 3'-deoxy-3'-C-formyl-beta-D-arabino-pentofuranosyl nucleosides 21 and 22. Desilylation afforded the 1-(3-deoxy-3-C-formyl-beta- D-lyxo-pentofuranosyl) 3',5'-O-hemiacetal nucleosides 33 and 34, respectively. Reduction of the formyl group of 21 and 22, followed by desilylation, yielded the 3'-deoxy-3'-C-(hydroxymethyl)-beta-D-arabino- pentofuranosyl) analogues 7 and 8, respectively. The uracil base moiety of 7 was converted to 5-iodouracil and then to (E)-5-(2-bromovinyl)uracil to furnish an analogue 10 of BVaraU. The 1-(3-deoxy-3-C-(hydroxymethyl)-beta-D-lyxo-pentofuranosyl) and 1-(2,3-dideoxy-3-C-(hydroxymethyl)-beta-D-erythro-pentofuranosyl) derivatives of uracil (31 and 6, respectively) and 5-iodouracil (32 and 9, respectively) were also obtained. All novel, fully deprotected nucleoside analogues were evaluated for antiviral activity against human immunodeficiency virus type-1, herpes simplex virus types-1 and -2, varicella zoster virus, human cytomegalovirus and influenza A. Of the compounds tested only (E)-5-(2-bromovinyl)-1-[3-deoxy- 3-C-(hydroxymethyl)-beta-D-arabino-pentofuranosyl]uracil (10) inhibited VZV (alone), but did so at concentrations well below the cytotoxicity threshold.

Animals↗
PubMed1980

Synthesis of certain [6:5:6] linear tricyclic nucleosides as potential antitumor agents.

A new class of tricyclic nucleosides in which the aglycon has a linear [6:5:6] geometry has been synthesized using certain pyrrolo[2,3-d]pyrimidine nucleosides as the starting materials. An adenosine-adenosine analogue (12) has been prepared from 6-aminotoyocamycin using two different synthetic routes. An adenosine-guanosine analogue (4) and several adenosine-6-mercaptopurine ribonucleoside-type tricyclic nucleoside derivatives have also been synthesized. Structural assignments have been based on 1H NMR spectral studies, as well as an unequivocal chemical proof of structure. An interesting chemical shift for the 2' hydrogen of certain tricyclic nucleosides was observed and is discussed. The in vitro cytotoxicity of these nucleosides against leukemia L-1210 has been determined. The in vivo evaluation of these tricyclic nucleosides against mouse leukemia will also be discussed.

Animals↗
PubMed1975

Nucleosides of 2-azapurines. 7 H-Imidazo[4,5-d]-1,2,3-triazines. 2.

A number of nucleosides of 2-azaadenine (4-amino-7H-imidazo[4,5-d]-1,2,3-triazine) were prepared by a previously described route, and some of these were deaminated by means of adenosine deaminase. Alternatively, nucleosides of 2-azahypoxanthine (7H-imidazo[4,5-d]-1,2,3-triazin-4(3h)-one) were prepared from hypoxanthine nucleosides by a 2-azahypoxanthine (7H imidazo[4,5]-1,2,3-triazin-4(3H)-one) were prepared from hypoxanthine nucleosides by a ring-opening and reclosure sequence. The cytotoxicity of these compounds to human epidermoid carcinoma No. 2 cells in culture and to certain resistant sublines thereof was determined. 2-Azaadenine nucleosides chan be metabolized to nucleotides, the cytotoxic agents, by two pathways, but the activity of the 2-azahypoxanthine nucleosides appears to result only from cleavage back to 2-azahypoxanthine.

Aza Compounds↗
PubMed2003

A combination chemical and enzymatic approach for the preparation of azole carboxamide nucleoside triphosphate.

Alternative substrates for DNA and RNA polymerases offer an important set of biochemical tools. Many of the standard methods for nucleoside triphosphate synthesis fail in the cases of nonpurine and nonpyrimidine nucleosides. An efficient preparation of the 5'-O-tosylates for both the deoxy- and ribonucleosides enabled preparation of the diphosphate esters by displacement with tris(tetra-n-butylammonium) pyrophosphate. Enzymatic synthesis of the azole carboxamide deoxyribonucleoside triphosphate was based on ATP as the phosphate donor, nucleoside diphosphate kinase as the catalyst, coupled with phosphoenol pyruvate (PEP) and pyruvate kinase as an ATP regeneration system. Ribonucleoside triphosphate synthesis required PEP as the phosphate donor and pyruvate kinase as the catalyst. An optimized purification procedure based upon boronate affinity gel was developed to yield highly purified nucleoside triphosphates. The strategy outlined here provides a new and efficient method for preparation of nucleoside 5'-triphosphate and is likely applicable to a broad variety of base and sugar modified nucleoside analogues.

Adenosine Triphosphate↗
PubMed2002

Synthesis of the tRNA(Lys,3) anticodon stem-loop domain containing the hypermodified ms2t6A nucleoside.

The synthesis of a protected form of the hypermodified nucleoside, N-[(9-beta-D-ribofuranosyl-2-methylthiopurin-6-yl)carbamoyl]threonine, (ms2t6A) is reported. The hypermodified nucleoside was subsequently elaborated to the protected nucleoside phosphophoramidite using a protecting group strategy compatible with standard RNA oligonucleotide chemistry. The phosphoramidite reagent was then used to synthesize the 17-nucleotide RNA hairpin having the sequence of the anticodon stem-loop (ASL) domain of human tRNA(Lys,3), the primer for HIV-1 reverse transcriptase. Introduction of the modification at position 37 of the tRNA ASL modestly decreases the thermodynamic stability of the RNA hairpin as has been seen previously for the prokaryotic t6A nucleoside lacking the 2-methylthio substituent. 2D NOESY NMR spectra of the ms2t6A containing tRNA ASL indicate that the threonyl side chain adopts a conformation similar to that seen in the solution structure of the analogous t6A containing E. coli tRNA(Lys), despite the presence of the bulky methylthio group. This synthetic approach allows for site-specific incorporation of the hypermodified nucleoside and should facilitate future studies directed at understanding the roles of nucleoside modification in modulating the stability and specificity of biologically important RNA-RNA interactions. Our synthesis of the ms2t6A containing RNAs demonstrates that this methodology is suitable for obtaining quantities of RNA required for structural studies of the HIV primer tRNA.

Anticodon↗
PubMed2006

New modular and efficient approach to 6-substituted pyridin-2-yl C-nucleosides.

A novel modular, efficient, and practical methodology of preparation of 6-substituted pyridin-2-yl C-nucleosides was developed. An addition of 2-lithio-6-bromopyridine 2b to TBDMS-protected 2-deoxyribonolactone 5 gave aduct 7 as an equilibrium mixture of anomeric hemiketals 1-(6-bromopyridin-2-yl)-1-hydroxynucleosides 7a,b and its open form 7c. Reduction of the adduct 7 with Et3SiH and BF3 x Et2O afforded the desired 6-bromonucleoside 8a as pure beta-anomer in a total yield of 32% over two steps from 5. Intermediate 8a was then subjected to a series of palladium catalyzed cross-coupling reactions and aminations to give a series of protected 1beta-(6-alkyl-, 6-aryl-, and 6-aminopyridin-2-yl)-2-deoxyribonucleosides 9. Catalytic hydrogenation of 8a gave an unsubstituted pyridine C-nucleoside, and diazotative oxodeamination of 6-aminopyridine nucleoside 9f by isopentyl nitrite in acetic acid gave 6-oxopyridine nucleoside 10i. Deprotection of silylated nucleosides 9 by Et3N.3HF gave a series of free C-nucleosides 10.

Hydrocarbons, Brominated↗
PubMed2006

Solid-phase synthesis of dinucleoside and nucleoside-carbohydrate phosphodiesters and thiophosphodiesters.

Unprotected nucleosides (ROH) were reacted with two polymers bound to N,N-diisopropylamino-1,3,2-oxathiaphospholane in the presence of 1H-terazole. Oxidation with tert-butyl hydroperoxide or sulfurization with Beaucage's reagent, followed by the 1,3,2-oxathiaphospholane ring opening with unprotected nucleosides or carbohydrates (R'OH) in the presence of DBU, afforded nucleoside-(5'-5')-nucleoside or nucleoside-carbohydrate phosphodiester and thiophosphodiester derivatives through the elimination of polymer-bound ethylene episulfide. This strategy offers the advantages of facile isolation of final products and monosubstitution of unprotected nucleosides and carbohydrates.

Carbohydrates↗
PubMed2005

Simple ethers as models of sugar molecules in calculations of vertical excitation energies of DNA and RNA nucleosides.

The ribose and deoxyribose molecules of RNA and DNA nucleosides are substituted with simple model compounds 1-methoxy-2-ethanol and 1-methoxypropane to mimic the effect of binding to sugars on the vertical excitation energies of purine and pyrimidine bases. The (R)-1-methoxy-2-ethanol, CH(3)OC*HCH(2)OH, for model ribose nucleosides and (R)-1-methoxypropane, CH(3)OC*HC(2)H(5), for model deoxyribose nucleosides have minimal structural characteristics of ribose and deoxyribose molecules when attached to nucleic acid purine and pyrimidine bases. The bases are attached to the C1 carbon atom designated by the asterisk. The vertical excitation energies of these model nucleosides are calculated with the time-dependent density functional theory method at the B3LYP level with 6-311++G(d,p) and aug-cc-pVDZ basis sets. The attachment of the ether molecules qualitatively and quantitatively modifies the excited state energy levels of the model nucleosides when compared to the free bases. These changes can affect the deexcitation mechanisms for photoexcited nucleosides.

DNA↗