Di(azacrown) conjugates of 2'-O-methyl oligoribonucleotides as sequence-selective artificial ribonucleases

Abstract

Functionalized 2‘-O-methyl oligoribonucleotides bearing two 3-(3-hydroxypropyl)-1,5,9-triazacyclododecane ligands attached via a phosphodiester linkage to a single non-nucleosidic building block have been prepared on a solid-support by conventional phosphoramidite chemistry. The branching units employed for the purpose include 2,2-bis(3-hydroxypropylaminocarbonyl)propane-1,3-diol, 2-hydroxyethyl 3‘-O-(2-hydroxyethyl)-β-d-ribofuranoside, and 2-hydroxyethyl 2‘-O-(2-hydroxyethyl)-β-d-ribofuranoside. Each of these has been introduced as a phosphoramidite reagent either into the penultimate 3‘-terminal site or in the middle of the oligonucleotide chain. The dinuclear Zn2+ complexes of these conjugates have been shown to exhibit enhanced catalytic activity over their monofunctionalized counterpart, the 3‘-terminal conjugate derived from 2-hydroxyethyl 3‘-O-(2-hydroxyethyl)-β-d-ribofuranoside being the most efficient cleaving agent. This conjugate cleaves an oligoribonucleotide target at a single phosphodiester ...