Conversion of Nucleoside H-Phosphonate Monoesters to the Corresponding H-Phosphonothioates. 31P NMR Studies

Abstract

³¹P NMR Studies on the conversion of nucleoside H-phosphonate monoesters into the corresponding H-phosphonothioates revealed that the key intermediate, the nucleoside trimethylsilyl pivaloyl phosphite 3, may undergo under the reaction conditions at least two parallel transformations to, most likely, the nucleoside trimethylsilyl chlorophosphite 6 and the monosilylated nucleoside H-phosphonate 5.     

Short Synthesis and Antiviral Activity of Acyclic Phosphonic Acid Nucleoside Analogues

An efficient route for synthesizing novel allylic and cyclopropanoid phosphonic acid nucleoside analogues is described. The condensation of the bromine derivatives 6 and 18 with nucleoside bases (A, U, T, C, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid nucleoside analogues. These compounds were evaluated for their antiviral properties against various viruses. Cyclopropanoid phosphonic adenine nucleoside analogue 23 showed significant anti-HIV activity.     

Synthesis and Structural Analysis of Oxadiazole Carboxamide Deoxyribonucleoside Analogs

Two novel C-linked oxadiazole carboxamide nucleosides 5-(2′-deoxy-3′,5′-β-D-erythro-pentofuranosyl)-1,2,4-oxadiazole-5-carboxamide (1) and 5-(2′-deoxy-3′,5′-β-D-erythro-pentofuranosyl)-1,2,4-oxadiazole-3-carboxamide (2) were successfully synthesized and characterized by X-ray crystallography. The crystallographic analysis shows that both unnatural nucleoside analogs 1 and 2 adapt the C2′-endo (“south”) conformation. The orientation of the oxadiazole carboxamide nucleobase moiety was determined as anti (conformer A) and high anti (conformer B) in the case of the nucleoside analog 1 whereas the syn conformation is adapted by the unnatural nucleoside 2. Furthermore, nucleoside analogs 1 and 2 were converted with high efficiency to corresponding nucleoside triphosphates through the combination chemo-enzymatic approach. Oxadiazole carboxamide deoxyribonucleoside analogs represent valuable tools to study DNA polymerase recognition, fidelity of nucleotide incorporation, and extension.

     

Nucleotide Analogues Containing the P-F Bond. An Overview of the Synthetic Methods a

Abstract

In this paper a short review is given of synthetic methods for the preparation of nucleoside phosphorofluoridates, nucleoside phosphorofluoridothioates and nucleoside phosphorofluoridodithioates.

     

Synthesis and Anti-HIV Activity of Novel 2′-Deoxy-2′-β-Fluoro-Threosyl Nucleoside Phosphonic Acid Analogues

Novel 2′-deoxy-2′-β-fluoro-threose purine phosphonic acid analogues were designed and racemically synthesized from 2-propanone-1,3-diacetate. Condensation successfully proceeded from a glycosyl donor 9 under Vorbrüggen conditions. Cross-metathesis of vinyl analogues 13 and 23 with diethyl vinylphosphonate yielded the desired nucleoside phosphonate analogues 14 and 24, respectively. Ammonolysis and hydrolysis of phosphonates yielded the nucleoside phosphonic acid analogues 16, 19, 26, and 29. The synthesized nucleoside analogues were subjected to antiviral screening against human immunodeficiency virus (HIV)-1. Adenine analogue 18 exhibited weak in vitro activities against human immunodeficiency virus (HIV)-1.     

Structure-Activity Relationships Among a New Class of Antiviral Heterosubstituted 2′,3′-Dideoxynucleoside Analogues

Abstract

3′-Oxa-4′-thiocytidine nucleoside analogues 14–17 were prepared from oxathiolanes 10 and 11, and evaluated for activity against HIV-1 and HBV in vitro. The nucleoside analogues were found to possess potent activities against HIV-1 in a panel of cell lines. Compound 16 is moderately active against HBV in 2.2.15 cells.     

Synthesis and Evaluation of Novel Oligodeoxynucleotides Containing 3′-C-(3-Benzoyloxypropyl)thymidine and Bicyclo Nucleoside Derivatives

Abstract

The stereoselective synthesis of 3′-C-Allyluridine derivative 2 has been accomplished. This nucleoside was used as a key synthon for the synthesis of oligodeoxynucleotides containing 3′-C-(3-benzoyloxypropyl)thymidine (X) or bicyclo nucleoside (Y+Z) monomers. Preliminary thermal experiments are reported.     

Synthesis and Hybridization Properties of Oligodeoxynucleotides Containing 3′-Deoxy-3′-C-methyleneuridine

Abstract

3′-Deoxy-3′-C-methyleneuridine nucleoside 1 ¹ has been incorporated into oligodeoxynucleotides. Relative to the unmodified references, oligomers containing nucleoside 1 displayed reduced binding affinities towards complementary DNA and RNA with a tendency towards RNA-selective hybridization.     

New Nucleoside Analogues for the Recognition of Pyrimidine-Purine Inversion Sites

Abstract

A new nucleoside designed to enhance triplex stability has been synthesised in 15 steps starting from sugar 2. This pathway contains the sugar derivative 9 which is a useful intermediate for the introduction of other natural and unnatural bases into the 2′-aminoethoxy nucleoside containing scaffold.     

A Convenient Synthesis of A Novel Nucleoside Analogue: 4-(δ-Diformyl-methyl)-1-(β-D-ribofuranosyl)-2-pyrimidinone

Abstract

The nucleoside analogue 4-(δ-diformyl-methyl)-1-(β-D-ribofuranosyl)-2-pyrimidinone (5) was prepared from the corresponding 4-methyl pyrimidinone nucleoside by means of the Vilsmeier reaction. The unprotected nucleoside can be phosphorylated directly with phosphorus oxychloride in triethyl phosphate.     

Synthesis of Novel Nucleoside Analogue Phosphorothioamidate Prodrugs and in vitro Anticancer Evaluation Against RKO Human Colon Carcinoma Cells

Novel phosphorothioamidates of pyrimidine nucleoside analogues have been prepared and evaluated in vitro against RKO human colon cancer cell by the MTT cytotoxicity assay. The parent nucleoside analogues were inactive in this assay, while the phosphorothioamidate prodrugs were active at low uM levels in some cases. The O-isopropyl phosphorothioamidate of 2 ′,3 ′-O-isopropylidene-uridine containing the L-phenylalanine ethyl ester 6f was the most active at 148 uM, a 10-fold enhancement in anticancer activity compared with the parent nucleoside 2 with no increase in cytotoxicity.     

Design and Synthesis of Novel Threosyl-5′- Deoxyphosphonic Acid Purine Analogues as Potent Anti-Hiv Agents

The discovery of threosyl phosphonate nucleoside (PMDTA, EC₅₀ = 2.53 μM) as a potent anti-HIV agent has led to the synthesis and biological evaluation of 5 ′-deoxyversions of threosyl phosphonate nucleosides from 1,4-dihydroxy-2-butene. The synthesized nucleoside phosphonic acid analogues 14 and 19 were tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 14 exhibits moderate in vitro anti-HIV-1 activity (EC₅₀ = 12.6 μM).     

An Unusual Iodine Monochloride Chlorination of an Imidazole Nucleoside

Abstract

The reaction of iodine monochloride with the imidazole nucleoside, 5-amino-1-(2,3,5-tri-0-acetyl-α-D-ribofuranosyl)imidazole-4-carboxamide, provides the 2-chloroimidazole nucleoside in good yield.     

Efficient Electrophilic Fluorination for the Synthesis of Novel 2′-Fluoro-3′-Methyl-5′-Deoxyphosphonic Acid Apiosyl Nucleoside Analogues

Novel 5′-deoxyapiosyl purine phosphonic acid analogues with a 2′-electropositive moiety, such as, a fluorine atom were designed and synthesized from commercially available hydroxylacetone. Condensation of a glycosyl donor 10 with purines under Vorbruggen conditions and cross-metathesis give the desired nucleoside phosphonic acid analogues 14, 17, 21, and 24. The synthesized nucleoside analogues were subjected to antiviral screening against HIV-1, and the adenine analogue 17 exhibited weak in vitro anti-HIV-1 activity (EC₅₀ = 26.6 μM)     

Studies on Reactions of Nucleoside H-Phosphonates with Bifunctional Reagents. Part VI. Reaction with Diols

Abstract

Reactions of nucleoside H-phosphonates with various diols using different types of condensing agents have been studied. Depending on the coupling procedure and the length of a polymethylene chain of the diol, acyclic H-phosphonate diesters or cyclic phosphite triesters were formed. The course of oxidation with iodine to produce cyclic nucleoside alkyl phosphotriesters or hydroxyalkyl nucleoside phosphodiesters can be controlled by the amount of water present in the reaction medium.     

Design,Synthesis and Anticonvulsant Activity of the Potent Adenosine Kinase Inhibitor GP3269

Abstract

The pyrrolopyrimidine nucleoside GP3269 (12) was shown to be a potent and selective inhibitor of human adenosine kinase (IC₅₀ = 11 nM) and to exhibit anticonvulsant activity in rats after oral administration. Synthesis of GP3269 was accomplished in 4 steps from 4-chloro-5-iodopyrrolopyrimidine (9) and the protected 5-deoxy-1-α-chlororibose (8) using a base-catalyzed nucleoside coupling reaction and the Suzuki reaction to replace the 5-iodo substituent with phenyl.     

Preparation of Nucleoside H-Phosphonoselenoate Monoesters Via the Phosphinate Approach

An efficient entry to nucleoside 3′-H-phosphonoselenoate monoesters via phosphinate intermediates was developed. It involves a reaction of suitably protected nucleosides with triethylammonium phosphinate in the presence of pivaloyl chloride, followed by selenization of the intermediate nucleoside phosphinates with triphenylphosphine selenide, to produce the corresponding nucleoside H-phosphonoselenoates in 86–92% yields.     

Synthesis of a Novel Aldehyde: 4-O-Methyl-5-formylmethyl- 2′-deoxyuridine

Abstract

The synthesis of the blocked nucleoside 3′,5′-di-O-p-toluoyl-4-O-methyl-5-formylmethyl-2′-deoxyuridine (19) was accomplishied in eleven steps from gamma-butyrolactone. This aldehyde, which should facilitate the synthesis of nucleosides containing ¹⁸F, was converted to the corresponding blocked dithianyl nucleoside (21), and also to 5-(2,2-difluoroethyl)-substituted derivatives of 2′-deoxyuridine and 2′-deoxycytidine.     

Carbocyclic Nucleosides with a Modified Cyclopentane Skeleton

Abstract

The aminoalcohol 4 has been converted into carbocyclic nucleoside analogues 2 and 3.     

2-Cyanoethyl H-Phosphonate. A Reagent for the Mild Preparation of Nucleoside H-Phosphonate Monoesters

Abstract

2-Cyanoethyl H-phosphonate was condensed with protected nucleoside derivatives and the cyanoethyl group subsequently removed by anhydrous base to give the corresponding nucleoside H-phosphonate in good yield.