Synthesis of Modified Nucleosides. Palladium-Catalysed Couplings of Organostannanes or Organoboranes with Pyrimidine Nucleosides

Abstract

Coupling of suitably protected 5-iodouridine or 5-iodo-2′-deoxyuridine with either arylboronic acids or aryltrimethylstannanes in the presence of a palladium catalyst gave moderate yields of the corresponding 5-aryluridines and 5-aryC2′-deoxyuridines. 5-Hydroxyuridine was converted into 5-(trifluoromethanesulphonyl)uridine in good yield and the triacetate of this modified nucleoside also underwent palladium-catalysed couplings with a variety of organostannanes to produce the 5-substituted uridine in excellent yield.     

Synthesis of Six-Membered Nucleoside Analogs. Part 1: Pyrimidine Nucleosides Based on the 1,3-Dioxane Ring System

Abstract

The synthesis of pyrimidine nucleosides, cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]uracil (4) cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]thymine (5) and cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]cytosine (6) and their corresponding trans isomers is described. Compound 4 showed modest, selective activity against human immunodeficiency virus in acutely infected primary human lymphocytes.     

Synthesis of 5-Tethered Carborane-Containing Pyrimidine Nucleosides as Potential Agents for DNA Incorporation

Abstract

Several 5-substituted-2′-deoxyuridines have been prepared in which the carborane moiety is attached at the terminus of a flexible hydrocarbon chain containing an ester linkage. These boron moieties as the B-10 enriched compounds have potentiality for use in the treatment of cancer by means of boron neutron capture therapy. A convenient synthetic route, in high yield, has been developed for the preparation of these 5-tethered carborane-containing pyrimidine nucleosides.     

A Convenient Synthesis of D-Psicofuranosyl Nucleosides1

Abstract

As part of our studies on the synthesis of conformationally restricted nucleosides of types 1 and 2, where X = CH₂, O or S, we required access to differentially substituted D-psicofuranosyl nucleosides such as 3. As shown in the table, we have developed a convenient approach to such compounds that depends on the direct condensation of the 1,2:3,4-di-O-isopropylidene-β-D-psicofuranose derivative 4 with an appropriate silylated purine or pyrimidine base.² Although the α and β anomers of 3 are formed in a 1:1 ratio, the yields of the β anomers are generally comparable with earlier condensation methods that use psicofuranosyl- halide², 2-benzoates⁴ or 2-nitro derivative⁵. However, the present method has the advantage that the starting sugar 4 is more readily accessible. The precursor 6′-alcohol can be prepared in very large amounts from D-fructose using the method of Prisbe et al.⁴     

Synthesis of 2-S-dioxo Isosteres of Purine and Pyrimidine Nucleosides. III. Alkyl And Glycosyl Derivatives of Triazolo-and Thiadiazolothiadiazines.

Abstract

Synthesis of methyl, glucosyl and ribosyl derivatives of 7-amino-2H, 4H-[1, 2, 3]triazolo [4, 5-c] [1, 2, 6] thiadiazine 5, 5-dioxide (1a) and 7-amino-4H- [1, 2, 5] thiadiazolo [3, 4-c][1, 2, 6] thiadiazine 5, 5-dioxide (2a) is described. The structures of the glycosyl derivatives are discussed on the basis of their PMR- and UV-spectroscopic data.     

The O18 antigens (lipopolysaccharides) of Escherichia coli. Structural characterization of the O18A, O18A1, O18B and O18B1-specific polysaccharides.

The O-specific polysaccharide moieties (PS) of the O18A, O18A1, O18B, and O18B1 antigens (lipopolysaccharides, LPS) consist of L-rhamnose (Rha), N-acetyl-D-glucosamine, D-galactose, and D-glucose in different molar ratios. By using chemical fragmentation, methylation, as well as one- and two-dimensional NMR spectroscopy, the structures of these polysaccharides were found to be [formula: see text] In O18A-PS and O18A1-PS x = 2, whereas in O18B-PS and in O18B11-PS x = 3. In all four polysaccharides alpha-D-Galp (residue D) is substituted at O-3. This substituent L (residue E) is beta-D-GlcpNAc-(1 in O18A-PS and O18A1-PS and it is alpha-D-Glcp-(1 in O18B-PS and O18B1-PS. Whereas there is no further substituent on the main chain of the O18A and O18B polysaccharides, in O18A1-PS and O18B1-PS the alpha-D-GlcpNAc residue A is substituted with alpha-Glcp-(1 (residue F), which is linked to O-6 in O18A1-PS and to O-4 in O18B1-PS. These results show that the O18 antigen comprises a group of four related LPS (O18A and O18B, with their glucosylated forms O18A1 and O18B1). The results are discussed with respect to epitope definition and biochemical implications.     

Synthesis and Biochemical Activity of 5-Tethered Carborane-Containing Pyrimidine Nucleosides as Potential Agents for DNA Incorporation

Abstract

Synthesis and biochemical evaluation of a series of 5-tethered carborane-containing pyrimidine nucleosides have been undertaken. The biochemical studies with human TK demonstrated that these compounds can be phosphorylated to the corresponding 5′-monophosphate and that the most significant conversion occurred when seven atoms were inserted between the carborane cage and the pyrimidine base, and of these the best was the one with saturated ester.     

Nucleosides,III1 Synthesis and Properties of 2-Trifluoromethyl-Naphthimidazole-Ribonucleoside

Abstract

The fusion reaction between 2-trifluoromethylnaphth[2,3-d]imidazole (1) and 1-0-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (2) leads to 2,3′,5′-tri-O-benzoyl-1-β-D-ribofuranosylnaphth[2,3-d]imidazole (3). Debenzoylation of (3) gives the corresponding nucleoside 1-β-D-ribofuranosyl -2-trifluoromethylnaphth[2,3-d]imidazole (4). Structural proofs are based on elementary analysis, UV-and ¹H-NMR spectra.     

Synthesis of 2-Bromomethyl-3-Hydroxy-2-Hydroxymethyl-Propyl Pyrimidine and Theophylline Nucleosides Under Microwave Irradiation. Evaluation of Their Activity Against Hepatitis B Virus

Alkylation of 2-methylthiopyrimidin-4(1H)-one (1a) and its 5(6)-alkyl derivatives 1b–d as well as theophylline (7) with 2,2-bis(bromomethyl)-1,3-diacetoxypropane (2) under microwave irradia-tion gave the corresponding acyclonucleosides 1-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]-2-methyl-thio pyrmidin-4(1H)-ones 3a–d and 7-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]theophylline (8), which upon further irradiation gave the double-headed acyclonucleosides 1,1 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis[(2-(methylthio)-pyrimidin-4(1H)-ones] 4a–c, and 7,7 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis(theophylline) (9). The deacetylated derivatives were obtained by the action of sodium methoxide. The activity of deacetylated nucleosides against Hepatitis B virus was evaluated. Compound 5b showed moderate inhibition activity against HBV with mild cytotoxicity.     

Novel Acyclic Analogues of Pyrimidine Nucleosides: 1-Methoxy-2, 3-Dihydroxypropyl and 1-Methoxy-3-hydroxypropyl Derivatives

Abstract

The preparation of a series of novel pyrimidine nucleoside analogues in which the N-1 ribosyl moiety is replaced by 1-methoxy-2, 3-dihydroxypropyl and 1-methoxy-3-hydroxypropyl substituents is described.     

Nucleosides,IV1 Synthesis and Properties of 2-Metylthio-Naphthimidazole-Ribonucleoside

Abstract

The synthesis of 2-Methylthio-1-(β-D-ribofuranosyl) naphthimidazole has been accomplished by condensation of 2-methylthio-1-trimethylsilylnaphthimidazole(3) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose(4) in the presence of trimethylsilyl triflate in 1,2-dichloroethane, followed by subsequent debenzoylation. Structural proofs are based on elementary analysis, UV- and ¹H-NMR-spectra.     

Labeled carbon dioxide (C18O2): an indicator gas for phase II in expirograms.

Carbon dioxide labeled with 18O (C18O2) was used as a tracer gas for single-breath measurements in six anesthetized, mechanically ventilated beagle dogs. C18O2 is taken up quasi-instantaneously in the gas-exchanging region of the lungs but much less so in the conducting airways. Its use allows a clear separation of phase II in an expirogram even from diseased individuals and excludes the influence of alveolar concentration differences. Phase II of a C18O2 expirogram mathematically corresponds to the cumulative distribution of bronchial pathways to be traversed completely in the course of exhalation. The derivative of this cumulative distribution with respect to respired volume was submitted to a power moment analysis to characterize volumetric mean (position), standard deviation (broadness), and skewness (asymmetry) of phase II. Position is an estimate of dead space volume, whereas broadness and skewness are measures of the range and asymmetry of functional airway pathway lengths. The effects of changing ventilatory patterns and of changes in airway size (via carbachol-induced bronchoconstriction) were studied. Increasing inspiratory or expiratory flow rates or tidal volume had only minor influence on position and shape of phase II. With the introduction of a postinspiratory breath hold, phase II was continually shifted toward the airway opening (maximum 45% at 16 s) and became steeper by up to 16%, whereas skewness showed a biphasic response with a moderate decrease at short breath holding and a significant increase at longer breath holds. Stepwise bronchoconstriction decreased position up to 45 +/- 2% and broadness of phase II up to 43 +/- 4%, whereas skewness was increased up to twofold at high-carbachol concentrations. Under all circumstances, position of phase II by power moment analysis and dead space volume by the Fowler technique agreed closely in our healthy dogs. Overall, power moment analysis provides a more comprehensive view on phase II of single-breath expirograms than conventional dead space volume determinations and may be useful for respiratory physiology studies as well as for the study of diseased lungs.     

Synthesis and Biochemical Activity of Hydrophilic Carborane-Containing Pyrimidine Nucleosides as Potential Agents for DNA Incorporation and BNCT

Abstract

A novel type of hydrophilic 5-tethered carborane-containing 2′-deoxyuridine derivative, SUB-7-DIOL, has been developed. This compound is a potential agent for DNA incorporation and BNCT, because it showed satisfactory aqueous solubility and demonstrated an excellent rate of phosphorylation by human thymidine kinase. This study also demonstrated the importance of tethering a flexible hydrocarbon chain between the carborane cage and the 5-position of the nucleoside, and the effectiveness of a water-solubilizing moiety attached to the carbon atom of the lipophilic carborane cage.     

Nucleosides LXXXIX. Synthesis of 1-(2-chloro-2-deoxy-alpha- and -beta-D-arabinofuranosyl)cytosines.

1-(2-Chloro-2-deoxy-beta-D-arabinofuranosyl)cytosine (16) and its alpha anomer (18) were synthesized by direct condensation of 3,5-di-O-acetyl-2-chloro-2-deoxy-alpha-D-arabinofuranosyl bromide with trimethylsilylated N-4-acetylcytosine in the absence of catalyst. A new and convenient method for the synthesis of 1,3,5-tri-O-acetyl-2-chloro-2-deoxy-alpha-D-arabinofuranose from methyl 3,5-di-O-benzyl-alpha,beta-D-ribofuranoside is described.     

Synthesis of 1,3-Dl-O-Acetyl-5-O-Benzoyl-2-O -(O-Carboran-1-Ylmethyl)- D-Ribofuranose. A General Precursor for the Preparation of Carborane-Containing Nucleosides for Boron Neutron Capture Therapy

Abstract

An eight-step synthesis of 1,3-di-O-acetyl-5-O-benzoyl-2-O-(o-carboran-1-ylmethyl)-D-ribofuranose 9 was carried out from 1,2:5,6-O-isopropylidene-α-D-allofuanose 1. Condensation of 9 with trimethylsilyl protected uracil in the presence of trimethylsilyl trifluoro-methanesulfonate, and subsequent deblocking of the resulting 1-[3-O-acetyl-5-O-benzoyl-2-O-(o-carboran-1-ylmethyl)-D-ribofuranosyl]uracil 10 (>95& β-configuration) by alkaline hydrolysis, yielded 1-[2-O-(o-carboran-1-ylmethyl)-β-D-ribofuranosyl]uracil 11.     

Radiolabelled Pyrimidine Nucleosides to Monitor the Expression of HSV-1 Thymidine Kinase in Gene Therapy

Abstract

Selective radiolabelling and imaging of transduced HSV tk expressing cells was studied using [¹²³I]IVFRU, [¹²⁵I]FIRU and [¹²⁵I]FIAU. Although all three radionucleosides accumulated in the KBALB-STK transduced murine tumour line in vitro and in vivo, [¹²⁵I]FIRU provided optimal performance in terms of selectivity for HSV tk expressing cells and % of injected dose accumulating in the tumor.     

Synthesis of 2S-Dioxo Isosteres of Purine and Pyrimidine Nucleosides IV. Selective Glycosylation of 4-Amino-5H-Imidazo [4, 5-c]-1, 2, 6-Thiadiazine 2, 2-Dioxide

Abstract

Selective glycosylation of 4-amino-5H-imidazo [4, 5-c]-1, 2, 6-thiadiazine 2, 2-dioxide (1) through its 1-benzyl derivative (2) is described. The structures of the compounds are discussed on the basis of ¹H nmr 2D homonuclear chemical shift correlations, NOE difference spectroscopy and iterative analyses.     

A Novel Route for the Synthesis of Fluorodeoxy Sugars and Nucleosides

Abstract

Ring-fluorination of α- and β-D-pentofuranosides containing free secondary hydroxyl groups by (diethylamino)sulfur trifluoride (DAST) was studied.     

Synthesis of 2-S-Dioxo Isosteres of Purine and Pyrimidine Nucleosides. V. 13 CDNMR Study of SYN-ANTI Equilibrium in a Glucoside of a N-Substituted Barbituric Acid Isostere

Abstract

Glycosylation of 2-(2-phenylethyl)-1, 2, 6-thiadiazin-3, 5-dione 1, 1-dioxide (1) via the “silyl method” is described. The reaction favours N-substitution and the tetra-O-acetyl-β-D-glucopyranoside 2 as well as the free nucleoside 3 have been isolated and characterized by UV and NMR studies. Nucleoside 2 exists as rotationally restricted syn-anti conformers at room temperature. From 13 CDNMR studies over the temperature range 234–333 K the enthalpy H⁺⁺ and entropy δS⁺⁺ of activation has been calculated.     

Conformational Analysis of Canonical 2-Deoxyribonucleotides. 1. Pyrimidine Nucleotides

Abstract

The molecular structure and relative stability of north and south conformers of 2′-deoxyribonucleotides containing pyrimidine nucleic acid bases (2′-deoxythymidilic (pdT), 2′- deoxycytidilic (pdC) acids and their mono- and dianions) have been obtained and analyzed at the DFT/B3LYP level using the standard 6–31G(d) basis set. We have revealed that, when the nucleobase moiety is incorporated into the nucleotides, it maintains a nonplanar and nonrigid conformation due to out-of-plane deformation of the amino group and pyrimidine ring. It has been demonstrated that an increase of negative charge of the phosphate group results in increase of amino group pyramidalization, discrimination between conformers with syn and anti orientation of base with respect to sugar, strengthening of intramolecular C-H…O hydrogen bonds leading to deformation and fixation of geometry of nucleotides, and weakening of phosphodiester bond. These results allow to make suggestions about sources of twist and buckle deformations of base pairs, mechanisms of repaire of DNA via change of base orientation, and conditions for breakage of the P-O bonds during hydrolysis.