Di(azacrown)Conjugates of 2'-O-Methyl Oligoribonucleotides as Sequence-Selective Artificial Ribonucleases

摘要

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)-beta-D-ribofuranoside,and 2-hydroxyethyl 2'-O-(2-hydroxyethyl)-beta-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 Zn~(2+)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)-beta-D-ribofuranoside being the most efficient cleaving agent.This conjugate cleaves an oligoribonucleotide target at a single phosphodiester bond and shows turnover and 1000-fold cleaving activity compared to the free monomeric Zn~(2+)chelate of 1,5,9-triazacyclododecane.