Novel route to oligo(deoxyribonucleoside phosphorothioates). Stereocontrolled synthesis of P-chiral oligo(deoxyribonucleoside phosphorothioates)

Abstract

The synthesis and separation of diastereoisomerically pure 5'-O-DMT-nucleoside 3'-0-(2-thio-1 ,3,2-oxathiaphospholane) allows their use as synthons in DBUcatalyzed reaction with the 5'-hydroxyl function of solid-support-bound nucleoside moiety. Since this reaction is stereospecific (>99%), this novel method allows preparation of oligo(nucleoside phosphorothioates) (1) with predetermined chirality at each P-chiral internucleotide phosphorothioate centre.

Application of antisense DNA method for the study of molecular bases of brain function and behavior

“…This may be due partly to the presence of stereoisomers and phosphorodithioates (in which two oxygen atoms are replaced with sulfur) which are now developed (Marshall and Caruthers, 1993;Stec et al, 1991;Zon and Geiser, 1991), although it is reported that the efficiency of phosphorodithioates as an antisense analogue is rather poor (Ghosh et al, 1993b). In addition, possible toxicity in the CNS is still controversial.…”

Inhibition of Gene Expression by Triple Helix Formation in Hepatoma Cells

“…48). The substitution for one of the nonbridging oxygen atoms of the internucleotide phosphate by sulfur produces a compound that is highly resistant to degradation by nucleases (49) and also creates a new stereogenic center (50,51). Phosphorothioate-modified oligonucleotide prepared by existing methodologies consists of the mixture of 2 n diastereomers where n is a number of phosphorothioate internucleotide linkage.…”

Stereodifferentiation—the effect of P chirality of oligo (nucleoside phosphorothioates) on the activity of bacterial RNase H

“…Moreover, the contribution of each diastereomer cannot be described by the 2-n relationship, because each step of chain elongation is slightly stereoselective (16). Our recently elaborated oxathiaphospholane method for the synthesis of PS-oligos is, thus far, the only one allowing P stereocontrolled chemical synthesis of oligo(nucleoside phosphorothioates) (17,18) longer than tetramers in either the Sp orRp configuration (19,20). Having this method of synthesis in hand we decided to check the influence of 'chirality' (21) of PS-oligos upon their proclivity towards RNA duplex formation and the response of RNase H towards double-stranded DNA-RNA structures containing PS-oligos of predetermined chiral sense (absolute configuration) at the phosphorus at each intemucleotide phosphorothioate function.…”