Synthesis and Biological Activities of 2′-Modified 4′-Thionucleosides

Abstract

We have synthesized 4′-thioDMDC, 4′-thiogemcitabine, and 4′-thioarabinonucleosides, as potential antitumor and antiviral agents, originated from D-glucose. Biological activities of these compounds are also described.     

Synthesis and Antiviral Evaluation of 3′-Substituted Thymidine Analogues Derived from 3′-Amino-3′-deoxythymidine

Abstract

To assess the structure-activity relationship for antiviral activity, a series of 3′-deoxy-3′-N-functionalized thymidine analogues were synthesized. Several of these thymidine analogues show moderate in vitro activity against HIV-1 and HIV-2.     

Synthesis and Biological Activity of 4′-Thionucleosides of 2-Chloroadenine1

Abstract

1,2,3,5-Tetra-O-acetyl-4-thio-D-riboruranose, prepared from 2,3,5-tri-O-benzyl-D-ribofuranose in four steps, was converted to the corresponding 2-chloroadenine nucleoside (8), which was deoxygenated to obtain 2-chloro-2′-deoxy-4′-thioadenosine (12). This is the first report of a 2′-deoxy-4′-thioribonucleoside of a purine rather than a pyrimidine. These novel nucleosides (8 and 12) were cytotoric to several human tumor cell lines in culture.     

An Improved Protection-Free One-Pot Chemical Synthesis of 2′-Deoxynucleoside-5′-Triphosphates

A facile, straightforward, reliable, and an efficient method for the gram-scale chemical synthesis of both purine deoxynucleotides such as 2 ′-deoxyguanosine-5 ′-triphosphate (dGTP) and 2 ′-deoxyadenosine-5 ′-triphosphate (dATP) and pyrimidine deoxynucleotides such as 2 ′-deoxycytidine-5 ′-triphosphate (dCTP), thymidine-5 ′-triphosphate (TTP), and 2 ′-deoxyuridine-5 ′-triphosphate (dUTP) starting from the corresponding nucleoside is described. This improved “one-pot, three step” Ludwig synthetic strategy involves the monophosphorylation of nucleoside followed by reaction with tributylammonium pyrophosphate and hydrolysis of the resulting cyclic intermediate to provide the corresponding dNTP in good yields (65%–70%).     

Different Strategies for the Synthesis of 2′- O -Aminoethyl Adenosine Building Blocks

The chemical modification of the 2′-O-position of nucleosides proved to be of great importance for the RNA stability. Greater stability of RNA duplexes allows a longer half life in the cell and, therefore, a better effect of RNA Interference. Here we investigated the synthesis of 2′-O-aminoethyl adenosine as a cationic modified building block.     

A New Synthesis of 2′,3′-Didehydro-3′-deoxy-3-Alkylthymidine

Abstract

The preparation of 3-alkyl D4T derivatives has been carried out starting from the corresponding 5′-O-t-butyldimethylsilyl-3′-O-methanesulfonylthymidine 2 by way of deprotection-elimination and succesive alkylation reactions.     

Synthesis of the 2′-,3′-Didehydro-2′-,3′-dideoxy and 2′-,3′-Dideoxy Derivatives of 6-Azauridine and a New Route to 2′-,3′-Didehydro-2′-,3′-dideoxy-5-chlorouridine

Abstract

The 5′-O-(4,4′-dimethoxytrityl) and 5′-O-(tert-butyldimethylsilyl) derivatives of 2′-,3′-O-thiocarbonyl-6-azauridine and 2′,3′-O-thiocarbonyl-5-chlorouridine were synthesized from the parent nucleosides by reaction with 4, 4′-dimethoxytrityl chloride and tert-butyldimethylsilyl chloride, respectively, followed by treatment with 1,1′-thiocarbonyldiimidazole. Introduction of a 2′-,3′-double bond into the sugar ring by reaction of the 5′-protected 2′-,3′-O-thionocarbonates with 1, 3-dimethyl-2-phenyl-1, 3, 2-diazaphospholidiine was unsuccessful, but could be accomplished satisfactorily with trimethyl phosphite. Reactions were generally more successful with the 5′-silylated than with the 5′-tritylated nucleosides. Formation of 2′-,3′-O-thiocarbonyl derivatives proceeded in higher yield with 5′-protected 6-azauridines than with the corresponding 5-chlorouridines because of the propensity of the latter to form 2,2′-anhydro derivatives. In the reaction of 5′-O-(tert-butyldimethylsilyl)-2′-,3′-O-thiocarbonyl-6-azauridine with trimethyl phosphite, introduction of the double bond was accompanied by N³-methylation. However this side reaction was not a problem with 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-O-thioarbonyl-5-chlorouridine. Treatment of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-6-azauridine with tetrabutylammonium fluoride followed by hydrogenation afforded 2′-,3′-dideoxy-6-azauridine. Deprotection of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-5-chlorouridine yielded 2′-,3′-didehydro-2′-,3′-dide-oxy-5-chlorouridine.     

Synthesis of 3′-4′-α-Propylene-2′-3′-dideoxynucleosides

Abstract

In order to obtain a high degree of rigidity within the sugar moiety of nucleosides, some bicyclic pyrimidine nucleoside analogues where synthesized starting from cyclopentanone. The C-4′-substituent is fused to the C-3′-position via a propylene to give a [3.3.0]-bicyclic ring system.     

Synthesis and Biological Activity of 3′-Modified 2′-5′ Adenylate Trimers

Abstract

One of the most important mediators in the mode of action of interferon is the (2′-5′)(A)n synthetase-RNase L pathway. The 2′-5′oligoadenylates (2–5A), synthesized from ATP, activate a pre-existing endonuclease that cleaves single-stranded RNA. The biological activity of 2–5A is rapidly lost due to cleavage of the 2′-5′ internucleotide bond by a specific 2′-5′-phosphodiesterase starting at the 3′end. This rapid cleavage and the poor uptake of 2–5A in intact cells limit the use of 2–5A as an antiviral or antineoplastic agent. Although several modified 2–5A analogues have been synthesized in order to improve the enzymatic stability, only few have proven to be resistant to degradation and still able to activate the 2–5A dependent endonuclease. 1-4 On the other hand, relative drastic methodology such as calcium coprecipitation, microinjection and liposome encapsulation5 has been used to introduce 2–5A into intact cells. Here, we present the synthesis and biological activity of oligoadenylates in which one or more adenosine residues were replaced by 9-(3-azido-3-deoxy-6-D-xylofuranosyl)adenine or 9-(3-amino-3-deoxy-D-xylofuranosyl)adenine. The oligonucleotides were synthesized by the phosphotriester method with triisopropylbenzenesulfonyl-chloride in the presence of N-methylimidazole as the condensing agent. The p-nitrophenylethyl group was used as the protecting group for the 2′-hydroxylfunction .(carbonate), the internucleotide linkage (phosphate ester) and the exocyclic amino groups of the heterocyclic base (carbamate). Bis(p-nitrophenylethy1)phosphoromonochloridate was used to phosphorylate the 5′-hy-droxyl group. All these blocking groups were removed with DBU in pyridine.     

A Direct and Efficient Synthesis of 5′-Deoxy-2′, 3′-

Abstract

A direct and efficient synthesis of 5′-deoxy-2′,3′-O-isopropylideneinosine, 7, from readily available inosine is described. An example of a potentially general synthesis of N -substituted-5′-deoxyadenosines from 7 is also described.     

An Improved Procedure for the Synthesis of 2′-0-Methylnucleoside 5′-Diphosphate

2′-0-Methyladenosine 5′-diphosphate has been chemically synthesized with an overall yield of 48% by adopting the direct phosphorylation of the nucleoside by phosphoryl chloride in step 1 and the morpholidate procedure in step 2 of the following scheme: Am¹ - pAm¹ (step 1) - ppAm (step 2). The method has been successfully used in the synthesis of 2′-O-methyluridine 5′-diphosphate and 2′-O-methylcytidine 5′-diphosphate and is applicable to the synthesis of nucleoside 5′-diphosphates in general.     

Synthesis of 3′-Amino-3′-deoxyguanosine 5′-Triphosphate

Abstract

Phosphorylation of 2′-0-acetyl-3′-trifluoroacetamido-3′-deoxy-N²-palmitoylguanosine with N-morpholino-O, O-bis(1-benzotriazolyl)phos-phate gives a 5′-phosphotriester. Removal of the benzotriazolyl group and addition of pyrophosphoric acid gave, after deblocking all protecting groups, GTP(3′NH₂).     

4-Thiofuranoid Glycals: Versatile Synthons for Stereoselective Synthesis of 4′-Thionucleosides

Abstract

β-anomers of 4′-thionucleosides have been synthesized stereoselectively, through PhSeCl- or N-iodosuccimide (NIS)-initiated electrophilic glycosidation to 3,5-O-(di-t-butylsilylene)-4-thiofuranoid glycal (1). This synthetic method has been applied to the synthesis of those analogues branched at the anomeric position using 1-C-carbon-substituted 3,5-O-(tetraisopropyldisiloxane-1,3-diyl)-4-thiofuranoid glycals (11–14) prepared based on lithiation of 10.     

Facile Protection-Free One-Pot Chemical Synthesis of Nucleoside-5′-Tetraphosphates

A new, straightforward, reliable, and convenient protection-free one-pot method for the synthesis of 2′-deoxynucleoside-5′-tetraphosphate and ribonucleoside-5′-tetraphosphate is reported. The present synthetic strategy involves the monophosphorylation of a nucleoside followed by reaction with tris-(tri-n-butylammonium) triphosphate and subsequent hydrolysis of the putative cyclic tetrametaphosphate intermediate to provide nucleoside-5′-tetraphosphate in moderate yield with high purity. A plausible mechanism is proposed to account for the formation of product.     

Synthesis of 3′-Amino and 5′-Amino Hydantoin 2′-Deoxynucleosides

Abstract

3′-Amino and 5′-amino derivatives of hydantoin 2′-deoxynucleosides have been prepared from the corresponding 3′-phthalimido and 5′-azido nucleosides, respectively, which in turn were prepared by condensation of appropriate sugars with 5-benzylidenehydantoin. The amino nucleosides were tested for their potential activity against HIV and HSV.     

Synthesis of 2′-Deuterio and 3′-Deuterio Cytidine 5′-Diphosphate

Abstract

2′-²H- and 3′-²H-CDP were synthesized from 5′-MMT-3′-O-TBDMS and 2′,5′- O-diTBDMS cytidine derivatives, respectively, by oxidation followed by acidic removal of 5′-protection, reduction with [NaBD(OAc)₃] and finally displacement of a tosyl group by pyrophosphate.