The impact of an extended nucleobase-2′-deoxyribose linker in the biophysical and biological properties of oligonucleotides

Interest in artificial DNA mimetics has been triggered by the widespread applications of nucleic acids as they are useful tools for modulation of the biophysical and biological properties of oligonucleotides. In this article, we describe the synthesis and properties of a novel thymine derivative (T*) containing an extended linker between the thymine nucleobase and the 2′-deoxyribose moiety. The modified 2′-deoxyribosyl derivative was prepared via coupling of a functionalized nucleobase to the amino group of 1-aminomethyl-2-deoxyribose, which was synthesized starting from an easily accessible cyano sugar available on a large-scale. Corresponding phosphoramidite and succinyl derivatives have also been incorporated into oligonucleotides at predetermined sites and defined internucleotidic motifs using the solid-phase synthesis approach. This derivative pairs equally well with adenine and guanine and it can be safely introduced at the 3′-end of the siRNAs to generate potent inhibitors of gene expression by the RNA interference mechanism

The impact of an extended nucleobase-2′-deoxyribose linker in the biophysical and biological properties of oligonucleotides

Interest in artificial DNA mimetics has been triggered by the widespread applications of nucleic acids as they are useful tools for modulation of the biophysical and biological properties of oligonucleotides. In this article, we describe the synthesis and properties of a novel thymine derivative (T*) containing an extended linker between the thymine nucleobase and the 2′-deoxyribose moiety. The modified 2′-deoxyribosyl derivative was prepared via coupling of a functionalized nucleobase to the amino group of 1-aminomethyl-2-deoxyribose, which was synthesized starting from an easily accessible cyano sugar available on a large-scale. Corresponding phosphoramidite and succinyl derivatives have also been incorporated into oligonucleotides at predetermined sites and defined internucleotidic motifs using the solid-phase synthesis approach. This derivative pairs equally well with adenine and guanine and it can be safely introduced at the 3′-end of the siRNAs to generate potent inhibitors of gene expression by the RNA interference mechanism.Financial support by the Spanish Ministerio de Ciencia e Innovacion (MICINN) (Projects CTQ2011-24237, CTQ2014- 55015-P, and CTQ2014-52588-R) and Principado de Asturias (Project FC-15-GRUPIN14-002) are gratefully acknowledged. CIBER-BBN is an initiative funded by the VI National R + D + i Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and Financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.Peer reviewe