SYNTHESIS AND EVALUATION OF GLUCURONIC-ACID DERIVATIVES AS ALKYLATING-AGENTS FOR THE REVERSIBLE MASKING OF INTERNUCLEOSIDE GROUPS OF ANTISENSE OLIGONUCLEOTIDES

2-Iodoethyl (methyl alpha-D-glucopyranosid)uronate and 2-iodoethyl (me thyl beta-D-glucopyranosid)thiouronate were prepared in five steps by an efficient synthetic route starting from D-glucuronic acid. Both com pounds were used to alkylate dithymidine phosphorothioate and phosphor odithioate diesters, leading to the corresponding phosphotriesters 12 to 15. Hydrolytic stability of 12-15 was studied in different biologic al media, The enzymatic hydrolysis of 12-15 was accompanied by another reaction resulting in formation of the dithymidine phosphodiesters. S everal possible mechanisms for these reactions are proposed. (C) 1997 Elsevier Science Ltd.