A New 1,5-Disubstituted Triazole DNA Backbone Mimic with Enhanced Polymerase Compatibility

Abstract

Triazole linkages (TLs) are mimics of the phosphodiester bond in oligonucleotides with applications in synthetic biology and biotechnology. Here we report the RuAAC-catalyzed synthesis of a novel 1,5-disubstituted triazole (TL 2 ) dinucleoside phosphoramidite as well as its incorporation into oligonucleotides and compare its DNA polymerase replication competency with other TL analogues. We demonstrate that TL 2 has superior replication kinetics to these analogues and is accurately replicated by polymerases. Derived structure–biocompatibility relationships show that linker length and the orientation of a hydrogen bond acceptor are critical and provide further guidance for the rational design of artificial biocompatible nucleic acid backbones.

Recent Developments in the Ruthenium‐Catalyzed Azide Alkyne Cycloaddition (RuAAC) Reaction

“…In a later study, the DNA backbone mimics 47 and 48 were prepared (Figure 12). These compounds are analogues of triazoles 45 and 46 in Scheme 20, but with a different sequence of atoms in the spacer [63b] . The stability of oligonucleotides containing a 6‐bond spacer was here confirmed, with oligonucleotides containing 47 forming more stable DNA and RNA duplexes compared to oligonucleotides with 48 incorporated.…”

A Visual Compendium of Principal Modifications within the Nucleic Acid Sugar Phosphate Backbone

“…However, triazole linkages are still being used, in particular, in the synthesis of oligomers from locked units [95], precisely because of the development of such a synthetic approach. Moreover, the biocompatibility of 1,5-disubstituted triazole linkages with DNA polymerases have been revealed recently [96].…”

Replacement of the phosphodiester backbone between canonical nucleosides with a dirhenium carbonyl “click” linker—a new class of luminescent organometallic dinucleoside phosphate mimics

“…There have been many examples of the phosphodiester backbone modifications reported in the literature. Relevant examples include phosphorothioate, 12,13 phosphoroamidate, 14 boranophosphate, 15,16 amide, 5,6,8,17,18 formacetal, 19 amine, 20 guanidinium, 21,22 and 1,2,3-triazole [23][24][25][26][27] internucleotide linkers.…”