Synthesis and evaluation of glucuronic acid derivatives as alkylating agents for the reversible masking of internucleoside groups of antisense oligonucleotides

Article abstract of DOI:10.1016/S0008-6215(97)00147-X

2-Iodoethyl (methyl α-D-glucopyranosid)uronate and 2-iodoethyl (methyl β-D-glucopyranosid)thiouronate were prepared in five steps by an efficient synthetic route starting from D-glucuronic acid. Both compounds were used to alkylate dithymidine phosphorothioate and phosphorodithioate diesters, leading to the corresponding phosphotriesters 12 to 15. Hydrolytic stability of 12-15 was studied in different biological media. The enzymatic hydrolysis of 12-15 was accompanied by another reaction resulting in formation of the dithymidine phosphodiesters. Several possible mechanisms for these reactions are proposed.