Dinucleoside Monophosphate Analogues Containing Disulfide Linkages

Abstract

Two dinucleoside monophosphate analogues containing disulfide linkages (1 and 2) have been prepared for incorporation into oligonucleotides. The modified oligomers will be tested for their potential as antisense agents.     

Monothiophosphate Analogs of Dinucleoside Tetraphosphate

Abstract

Monothiophosphate analogs of dinucleoside tetraphosphates have been synthesized i n order to study their resistance towards the specific hydrolase of E. Coli.     

Isosteric Phosphonate Pyrrolidine-Based Dinucleoside Monophosphate Analogues

Abstract

A novel α- and β-configured pyrrolidine nucleoside phosphonates in adenine series were synthesized from trans-4-hydroxy-L-proline as starting material. d(ApA) analogues were also prepared and studied with respect to their hybridization properties with polyU.     

Studies on the Stability of Dinucleoside H-Phosphonates

Abstract

The stability of two dinucleoside H-phosphonates under various conditions is reported.     

Studies Towards Synthesis of Dinucleoside Arylphosphonates with Metal Complexing Properties

Abstract

An efficient and stereospecific synthesis of dinucleoside 4′-(2,2′:6′,2″-terpyridyl)phosphonate 2 and 5-(2,2′-bipyridyl)phosphonate 3 via a palladium(0) cross coupling strategy has been developed.     

Synthesis of a Non-Hydrolyzable Dinucleoside Analogue

Abstract

A non-hydrolyzable dinucleoside analogue 31, which bears an internucleoside thioether linkage, was prepared from the branched-chain nucleoside precursors 26 and 28. Previous attempts to form the sulfide by the displacement of a 5′-mesyl group by thiol gave unsatisfactory results. In the course of preparing 28, it was found that the Vorbruggen coupling of 5-thiosugar 8 and persilylated base results in competing thiopyranone enol acetate formation.     

Synthesis of Dinucleoside Boranophosphates by a Boranophosphotriester Approach

Abstract

Dinucleoside boranophosphates including four kinds of nucleobases were synthesized by a boranophosphotriester method in good yields. In the present boranophosphotriester method, side-reactions at the nucleobases, which caused by a borane reagent, were completely avoided.     

Dinucleoside Monophosphates Containing AZT and 1-Methyladenosine or 7-Methylguanosine

Abstract

Dinucleoside monophosphates containing AZT and 1-methyladenosine or 7-methylguanosine were synthesized and their in vitro anti-HIV activity was determined.     

Dinucleoside Polyphosphate NAD Analogs as Potential NMN Adenylyltransferase Inhibitors. Synthesis and Biological Evaluation

Abstract

Two dinucleoside polyphosphate NAD analogs, P¹-(adenosine-5′)-P³-(nicotinamide riboside-5′)triphosphate (Np₃A, 1) and P¹-(adenosine-5′)-P⁴-(nicotinamide riboside-5′)tetraphosphate (Np₄A, 2), were synthesized and tested as inhibitors of both microbial and human recombinant NMN adenylyltransferase. Compounds 1 and 2 proved to be selective inhibitors of microbial enzymes.     

Triarylmethyl Substituted 4,5-Dicyanoimidazoles as Activators for Rp-Diastereoselective Synthesis of TpN Dinucleoside Methylphosphonates

Abstract

2-Triarylmethyl-4,5-dicyanoimidazoles 1–3 were synthesized and tested as activators in the methylphosphonamidite approach. TpN dinucleoside methylphosphonates generated showed diastereoselectivity of up to 8 / 1 (Rp / Sp). The influence of the different triarylmethyl substituents on diastereoselectivity is shown.     

Variability in the Geometry of RNA Double Helices Generated from Dinucleoside Building-Blocks

Abstract

A graphical method is presented for the generation of helical parameters from single-crystal structures of RNA nucleic acid fragments that are minimally dinucleosides. The method is compared with other published procedures, for a number of text examples. The RNA double helices generated from three different salts of the dinucleoside monophosphate GpC are examined in relation to the variations in helix morphology that are produced. It is shown that small differences between these GpC salts can be amplified to very distinct helix characteristics.     

Synthese Regiospecifique d'Un Dinucleoside Ponte: (O6 Desoxyguanosnyl)-1(N4-desoxycytidyl)-2 Ethane

Abstract

Appropriate protected deoxyguanosine and deoxyuridine derivatives, respectively activated at 0⁶ and. 0⁴ positions by the 3-nitro 1,2,4-triazol 1-yl group, were reacted with ethylene gtycol, ethylenediamine or ethanolamine to give monoalkylated nucleosides or cross-linked dimers or cross-linked dinucleosides.     

Regiospecipic Synthesis of a New Cross-Linked Dinucleoside : 1-(N6-Deoxyadenyl)-2-(o4-Thymidyl)-Ethane

Abstract

The bridged dinucleoside 1-(N⁶-deoxyadenyl) 2-(O⁴-thymidyl)-ethane was prepared from the nucleophilic substitution of a O⁴-triazo-lyl thymidine by a N⁶-(2-hydroxyethyl) deoxyadenosine derivative via the corresponding 6-halogeno hypoxanthine in ribose and deoxyribose series.     

Methodology for the Synthesis of Dinucleoside Monophosphates Containing A 2′-Deoxy-3-Isoadenosine Unit: 3-iso-dApT and Tp(3-iso-dA)

Abstract

2′ -Deoxy-3-isoadenylyl(3′-5′)thymidine and thymidylyl-(3′-5′)-2′-deoxy-3-isoadenosine have been synthesized by mild protection/deprotection methodology that circumvents facile N3-Cl′ hydrolytic cleavage of the 2′-deoxy-3-isoadenosine moiety.

     

Molecular Mechanics Studies of Dinucleoside Methylphosphonates: Influence of Methylphosphonate and its Chirality on the Phosphodiester Conformation

Abstract

Molecular mechanics studies are performed on single stranded as well as base paired forms of dinucleoside methylphosphonates comprising different base sequences for both the Sand R-isomers of methylphosphonate (MP). S-MP produces noticeable distortions in the geometry, locally at the phosphate center, and this enables the stereochemical feasibility of compact g^? g^? phosphodiester. Besides, it tends to perturb the conformations around the P- 03′ and glycosyl bonds, causing minor variations in stacking interactions. In single stranded dinucleosides, the gain in adjacent base stacking interaction energies seems to be sufficient to overcome the barrier to P-03′ bond rotation arising due to S-MP…sugar interaction, and this results in transition to a compact phosphodiester (B_I-type) from an initial extended phosphodiester (B_II-type) conformation. Such a thing seems rather difficult in base pair constrained duplexes. Dinucleosides with R-MP behave analogous to normal phosphate duplexes as the methyl group is away from the sugar. It is found that dinucleoside methylphosphonates are energetically less favoured than the corresponding dinucleoside phosphates mainly due to the depletion of contributions from electrostatic attractive interactions involving the base and sugar with the methylphosphonate consequent to the nonionic nature of the latter. Neither S-MP nor R-MP seem to significantly alter the stereochemistry of duplex structure.     

New Dinucleoside Analogues via Cross-Coupling Metathesis

Synthesis of 3′-3′, 5′-5′, and 3′-5′ dimeric thymidine, linked by an olefinic chain between glycosidic moieties is described. Cross metathesis reaction of 3′ or 5′ O-allyl analogues of thymidine led to the expected 3′-3′ and 5′-5′ dimeric compounds, respectively. In order to obtain the 3′-5′ dimer, 5′-O-allyl and 3′-O-allyl monomers were first linked by their free 3′ OH and 5′ OH groups through a glutaryl spacer; ring closing metathesis was then operated upon this temporary dimer, followed by glutaryl removal.     

Synthesis of Guanylyl (3′→5′)-5-methylcytidine (Gpm5C), a Dinucleoside Monophosphate which is Unable to Function as a Primer in the Synthesis of RNA by the Influenza A Virus RNA Polymerase

Abstract

Guanylyl (3′→5′)-5-methylcytidine (Gpm⁵C) has been synthesized enzymatically through the use of T₁RNAse at high enzyme dilution. In contrast with GpC, the methylated dinucleoside monophosphate is shown to be inactive as a primer for RNA synthesis by the RNA-dependent RNA polymerase of Influenza A virus.     

Visualization of Drug-Nucleic Acid Interactions At Atomic Resolution. VIII. Structures of Two Ethidium/Dinucleoside Monophosphate Crystalline Complexes Containing Ethidium: Cytidylyl(3′-5′) Guanosine

Abstract

This paper describes two complexes containing ethidium and the dinucleoside monophosphate, cytidylyl(3′-5′)guanosine (CpG). Both crystals are monoclinic, space group P2₁, with unit cell dimensions as follows: modification 1: a = 13.64 Å, b = 32.16 Å, c - 14.93 Å, β = 114.8° and modification 2: a = 13.79 Å, b = 31.94 Å, c = 15.66 Å, β = 117.5°. Each structure has been solved to atomic resolution and refined by Fourier and least squares methods; the first has been refined to a residual of 0.187 on 1,903 reflections, while the second has been refined to a residual of 0.187 on 1,001 reflections. The asymmetric unit in both structures contains two ethidium molecules and two CpG molecules; the first structure has 30 water molecules (a total of 158 non-hydrogen atoms), while the second structure has 19 water molecules (a total of 147 non-hydrogen atoms). Both structures demonstrate intercalation of ethidium between base-paired CpG dimers. In addition, ethidium molecules stack on either side of the intercalated duplex, being related by a unit cell translation along the a axis.

The basic feature of the sugar-phosphate chains accompanying ethidium intercalation in both structures is: C3′ endo (3′-5′) C2′ endo. This mixed sugar-puckering pattern has been observed in all previous studies of ethidium intercalation and is a feature common to other drug-nucleic acid structural studies carried out in our laboratory. We discuss this further in this paper and in the accompanying papers.     

Nucleic Acid Conformation: Crystal Structure of a Naturally Occurring Dinucleoside Phosphate (UpA)

THEORIES of the molecular structure of nucleic acids have so far been based on evidence from the crystal structures of monomeric units such as nucleosides and mononucleotides, the interpretation of diffraction patterns of oriented nucleic acid fibres and molecular model building^1–6. Such approaches can help to suggest structures of periodic molecules such as helices, but they are insufficient for predicting and understanding nonrepetitive structures such as the loops in transfer RNA (tRNA), presumably associated with many of the functions of tRNA. To understand the geometry of nucleic acids and possible constraints on their conformation, it is therefore essential to know the detailed conformation of the sugar residues and the conformational relationship between the sugar residue, the base and the phosphate group^7–9. The simplest molecule which contains this information is a 3´5´-dinucleoside phosphate. We now report the structure of uridine-3´,5´-adenosine phosphate (UpA). This is the first naturally occurring dinucleoside phosphate whose crystal structure has been determined by X-ray diffraction. The only other dinucleoside phosphate with known crystal structure is adenosine-2´,5´-uridine phosphate¹⁰, but it does not have the naturally occurring 3´5´ sugar phosphate linkage.     

A proposal for a convenient notation for P-chiral nucleotide analogues. Part 2. Dinucleoside monophosphate analogues

A configuration of ligands around a phosphorus atom in P-chiral dinucleoside monophosphate analogues can be described using D_P/L_P stereochemical notation, which allows immediate correlation between the notation of configuration and the actual spatial arrangement of the phosphorus ligands. The area of applications of this new stereochemical nomenclature covers dinucleoside units bridged by virtually any type of tri-and tetra-coordinated phosphorus moieties, that is, phosphorothioates, phosphoramidates, phosphoramidites, boranephosphates, methanephosphonates, H-phosphonates, and many others.