New Zwitterionic Oligonucleotides: Preparation and Complementary Binding

New zwitter-ionic oligonucleotide derivatives containing 1,2,3,4-tetrahydroisoquinoline-7-sulfonyl phosphoramidate group are described. Automated synthesis of these compounds was carried out according to the β-cyanoethyl phosphoramidite scheme using the Staudinger reaction between 2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl azide and phosphite triester within an oligonucleotide grafted to a polymer support. 1,2,3,4-Tetrahydroisoquinoline-7-sulfonyl phosphoramidate group (THIQ) proved to be stable under the conditions of standard oligonucleotide synthesis, including the removal of protective groups and cleavage of the oligonucleotide from the polymer support by treatment with a mixture of concentrated aqueous solutions of ammonia and methylamine (1 : 1) at 55oC. Oligonucleotides modified by one to five THIQ groups in various positions were obtained. The zwitter-ionic character of the obtained derivatives was reflected in their different mobility under conditions of denaturing PAGE. The thermal stability of the duplexes of oligodeoxynucleotides containing THIQ groups with complementary DNA and RNA differed only slightly from that of natural DNA:DNA and DNA:RNA duplexes. The results obtained suggest the possible use of oligonucleotides modified with zwitterionic THIQ groups as antisense therapeutic agents.