The synthesis of di- and oligo-nucleotides containing a phosphorodithioate internucleotide linkage with one of the sulfur atoms in a 5′-bridging position

Abstract

A new type of internucleotide phosphorodithioate linkage is described, wherein one of the sulfur atoms occupies a 5′-bridging position. Representative dinucleotides possessing such a bond were synthesized by S-alkylation of nucleoside-3′-O-phosphorodithioates with 5′-halogeno-5′-deoxy-nucleosides. A fully protected dithymidylate containing internucleotide 5′-S-phosphorodithioate linkage was converted into a 3′-O-phosphoramidite derivative and employed for introduction of a modified dinucleotide into a predetermined position of the oligonucleotide sequence. The 5′-S-phosphorodithioate linkage in dinucleotide analogues was found to be resistant toward nucleolytic degradation with snake venom PDE and nuclease P1. However, P-stereoselective degradation was observed for diastereomers of 5′-S-phosphorodithioate dithymidine analogs under treatment with calf spleen PDE. The new 5′-S-phosphorodithioate linkage was readily degraded by iodine solutions in the presence of water. It was also found that oligothymidylates containing a single 5′-S-phosphorodithioate linkage form much weaker duplexes with their complementary sequences.