Nucleosides, phosphorothioate

Preparation of nucleoside phosphorothioates, phosphorodithioates, and related compounds 91MI50. 

The nucleoside phosphorothioate (66 equation 43) reacts with tributylammonium phosphate in the presence of silver nitrate to give the nucleoside 5 -diphosphite (67). ... 

Detailed studies on the stereocontrolled synthesis of oligo(nucleoside phosphorothioate by the oxathiaphospholane approach were performed with monomers 15 [20].The optimization ofthe coupling step was performed [20,23] involving the amount of the monomer (20 mg for 1 pmol synthesis), the concentration of DBU (1 mol/1) and the coupling time (450 s). To complete the pro-... 

A new H-phosphonothionylating reagent, 9-fluorenemethyl H-phospho-nothioate (23) has been developed for the preparations of nucleoside H-phospho-nothioate 24 nucleoside phosphorothioate 25, and nucleoside phosphorodithioate 26. ... 

The first and clearest example of the use of nucleoside phosphorothioates to determine coordination geometry at an active site was the work of Jaffe and Cohn on hexokinase (22). They found that (7 p)-ATP)3S is a far better substrate with Mg(II) as the activating cation than with Cd(Il) however, (5p)-ATP/3S is a far better substrate with Cd(ll) than with Mg(ll) as the metal ion. That is, the favored complex depended on both the metal ion and the configuration at P of ATP/8S, and a change in metal ion from Mg(II) to Cd(II) led to a change in selectivity for the configuration at P. The structures of the preferred substrates were thereby deduced as those shown below. The other isomers, Mg(Sp)-ATP/3S and Cd(7 p)-ATP)8S, were less active or practically inactive. By the simplest interpretation of the data, both active complexes were the A-screw sense isomers shown here, in which Mg is coordinated to oxygen in one and Cd is coordinated to sulfur in the other. 

Syntheses of nucleoside phosphorothioates and -dithioates have been reviewed. 

It is a well established property that many enzymes interact in a stereospecific manner with the different diastereoisomers of nucleoside phosphorothioates. For example, when AMP is substituted by adenosine S -t7-monopho phorothioate (AMPS), adenylate kinase-catalysed phosphorylation occurs specifically at the pro-R oxygen atom to give (5ip)-ADPaS. The stereospecificity results from the restricted orientation of the P-O and P-S bonds in the enzyme active site. While it is known that changing the metal ion can perturb the stereoselectivity, Tsai and... 

The relative proportions of furanose and pyranose forms of aqueous 2-deoxy-2-fluoro-D-ribose at equilibrium have been determined with the help of H-, C-, and F-NMR spectroscopy.Recordings of vicinal C- P coupling constants were crucial for the determination of the configuration at phosphorus in the enantiomerically pure nucleoside phosphorothioates 40. After reassignment of the resonances for the phosphorus atoms in D-myn-inositol 1,2,6-trisphosphate, conclusions regarding the structure of its zinc complexes drawn previously on the basis of P-NMR titrations have been revised. 

Kraszewski et al. [208] have developed a new, efficient method for the synthesis of phosphorothioate diester, based on the H-phosphonate chemistry. The reaction of aryl nucleoside H-phosphonate with elemental sulfur furnished the corresponding aryl nucleoside phosphorothioate. The synthesis of phosphorothioates can be carried out as a four-components-one-pot reaction, by allowing nucleoside H-phosphonate to react with phenols in the presence of diphenyl phosphorochloridate to furnish aryl nucleoside H-phosphonates, which react with elemental sulfur. 

Nucleoside H-phosphorothioates of type 2 were synthesized by reacting unprotected nucleoside H-phosphonates 1 with elemental sulfur, suspended in pyridine containing tri-ethylamine and trimethylsilyl chloride [209]. After 5 min, the starling compounds were completely converted into nucleoside phosphorothioate. 

Biological activity is associated with isomerisation from thiono to thiolo forms (Chapter 12.12). Nucleoside phosphorothioates (RO)2POS are sometimes used to investigate enzyme mechanisms since they react more slowly than their oxy analogues (R0)2P02 (Chapter 11.4). 

As regards the modification of intemucleosidic links, bis(deoxynucleosidyl)-trimethylsilyl phosphites 190 can be converted to phosphorofluoridates 191 by the use of S02C1F,230 and dibenzoyltetrasulfide has been advocated as a rapid sulfur transfer agent in the synthesis of nucleoside phosphorothioates, being used to prepare a phosphorothioate after each cycle of a phosphoramidite synthesis.231 Oxidation of intemucleosidic H-phosphonothioates (2 -deoxy series) with iodine in aqueous acetonitrile in the presence of trimethylamine gives... 

Dahl, O. (1991) Preparation of nucleoside phosphorothioates, phosphorodithioates and related compounds Sulfur Reports 11, and references cited therein, 167-192. 

These otherwise promising results have been overwhelmed by a new strategy recently developed for the synthesis of oligo(nucleoside phosphorothioate)s (33). It has been proven that reaction of 5 -0-... 

Fig. 4 Synthesis of individual homochiral oligo(nucleoside phosphorothioates). 1 = DBU/acetonitrile ii = Ac20/2,6-lutidine, yV-methyl imidazole Hi=dichloroacetic acid/methylene chloride iv = 25% ammonium hydroxide.

Stereocontrolled Synthesis of Oligo(Nucleoside Phosphorothioates) (OligoS)... 

Fuji, M, Ozaki, K., Sekine, M., and Hata, T. (1987) Acylphosphonates 7 A new method for stereospecific and stereoselective generation of dideoxyribo-nucleoside phosphorothioates via the acylphosphonate Intermediate. Tetrahedron 43, 3395-3407... 

Stec, W. J. Wilk, A. Stereocontrolled Synthesis of 01igo(nucleoside phosphorothioate)s. Angew. Chem. Int. Ed. Engl. 1994, 33, 709-722... 

This chemistry has additionally been utilized in the preparation of nucleoside phosphorothioates," Reaction of (6) with NaH to remove the P-anilido group followed by CS2 gave the corresponding 5 -monomethoxytritylthymidine 3 -0-phenylphosphorothioate (as a mixture of diastereomers, 8) which was converted to the 5-methyl ester (9) (eq 4). Owing to the chiral... 

Figure 3. Effect of psoralen-conjugated oligo(nucleoside phosphorothioate)s (PS-S-Oligo) on the proliferation of human cervical carcinoma cell, C4II. and SiHa. [A] C4II cell line. PS-P-As without UVA-irradiation (4-), PS-P-scr without UVA-irradiation (A ), PS-P-As with UVA-irradiation ( ), PS-P-scr with UVA-irradiation (A). [B] SiHa cell line. PS-P-As without UVA-irradiation ( ), PS-P-scr without UVA-irradiation (A), PS-P-As with UVA-irradiation ( ), PS-P-scr with UVA-irradiation (A). UVA-irradiation 365nm, I.lmJ/cm sec. Cell growth was evaluated by modified MTT assay.

---