Synthesis of Nucleoside α-Thiotriphosphates via an Oxathiaphospholane Approach^†

Abstract

[reaction: see text]. Nucleoside 5'-O-(alpha-thiotriphosphates) were obtained in reactions of the appropriate nucleoside 5'-O-(2-thio-1,3,2-oxathiaphospholanes) with pyrophosphate in the presence of DBU. The presented method allows also for preparation of alpha-seleno congeners and corresponding alpha-modified diphosphates.

Towards mRNA with superior translational activity: synthesis and properties of ARCA tetraphosphates with single phosphorothioate modifications

“…Pathway B was excluded as nucleoside 5'- O -(1-thiodiphsophates) can be obtained by procedures similar to those for 5'- O -(1-thiotriphosphates), however, with lower yields 28,45. Moreover, nucleoside diphosphates are available from corresponding activated monophosphates used in pathway A.…”

Nucleotide Pyrophosphatase/Phosphodiesterase 1 Is Responsible for Degradation of Antisense Phosphorothioate Oligonucleotides

“…Adenosine 5Ј-(␣-thio)triphosphate (ATP(S) and cytidine 5Ј-(␣-thio)triphosphate (CTP␣S) were obtained as the S P isomers after enzymatic phosphorylation of AMPS and CMPS by adenylate and pyruvate kinases (Connolly et al, 1984;Koziolkiewicz et al, 2002). Deoxyadenosine 5Ј-(␣-thio)triphosphate (dATP␣S) was synthesized as a mixture of diastereomers (Misiura et al, 2005), which were separated using high-performance liquid chromatography (HPLC; an ODS Hypersil column, 4.6 ϫ 260 mm) using a linear gradient of 0-10% CH 3 CN/0.1 M triethyl ammonium bicarbonate (TEAB) pH 7.4, 0.33%/minute at a flow rate 1 mL/min. The retention times for the S P and R P isomers were 20.85 and 21.85 minutes, respectively.…”

“…For more detailed analysis of the inhibitory effect observed for nucleside (␣-thio)triphosphates, we carried out additional experiments using the R P and S P diastereomers synthesized by the oxathiaphospholane method (Misiura et al, 2005). Inhibitory effects of the dATP␣S diastereomers expressed as their IC 50 values are presented in Table 5.…”

Diastereomerically pure nucleoside‐5′‐O‐(2‐thio‐4,4‐pentamethylene‐1,3,2‐oxathiaphospholane)s—Substrates for synthesis of P‐chiral derivatives of nucleoside‐5′‐O‐phosphorothioates

“…16,17 On the other hand, because chromatographic separation of nucleoside-5 0 -O-oxathiaphospholane monomers, carrying typical protecting groups at the 3 0 -or 2 0 -and 3 0 -hydroxyl functions, could not be achieved, numerous P-chiral biophosphates were synthesized using unresolved monomers (e.g., 8, Scheme 3). [18][19][20] Here, we report on the synthesis of selected 3 0 -O-acylated deoxyribonucleoside-and 2 0 ,…”

“…29 As mentioned in the Introduction, NDPs and NTPs are biologically important compounds and their diastereomerically pure P-chiral analogs are useful tools in biochemi-cal studies. Our earlier experiments 18 showed that 3 0 -O-acetyl-thymidine-5 0 -O-(2-thio-1,3,2-oxathiaphospholane) (8, unseparated mixture of P-diastereomers) reacted with the phosphate and pyrophosphate anions to yield the corresponding 5 0 -O-(a-thiodiphosphate) (Scheme 3) and 5 0 -O-(a-thiotriphosphate), respectively.…”