Novel Short Oligonucleotide Conjugates as Inhibitors of Human Telomerase

Abstract

A series of oligonucleotide conjugates were designed and synthesized as novel inhibitors of human telomerase. These compounds contain a relatively short (6–7-mer) oligonucleotide domain, with an N3′ → P5′ phosphoramidate (np) or thio-phosphoramidate (nps) backbone, targeted to the template region of the RNA component of the enzyme and various pendant groups attached to either their 5′- or preferably to the 3′- termini. The most potent compounds in the series inhibited telomerase with low nM IC₅₀ values in biochemical assays whereas the cognate oligonucleotides without the pendant groups were significantly less active having IC₅₀ values 100-1000-fold higher.