Triazole-Modified Nucleic Acids for the Application in Bioorganic and Medicinal Chemistry

Abstract

This review covers studies which exploit triazole-modified nucleic acids in the range of chemistry and biology to medicine. The 1,2,3-triazole unit, which is obtained via click chemistry approach, shows valuable and unique properties. For example, it does not occur in nature, constitutes an additional pharmacophore with attractive properties being resistant to hydrolysis and other reactions at physiological pH, exhibits biological activity (i.e., antibacterial, antitumor, and antiviral), and can be considered as a rigid mimetic of amide linkage. Herein, it is presented a whole area of useful artificial compounds, from the clickable monomers and dimers to modified oligonucleotides, in the field of nucleic acids sciences. Such modifications of internucleotide linkages are designed to increase the hybridization binding affinity toward native DNA or RNA, to enhance resistance to nucleases, and to improve ability to penetrate cell membranes. The insertion of an artificial backbone is used for understanding effects of chemically modified oligonucleotides, and their potential usefulness in therapeutic applications. We describe the state-of-the-art knowledge on their implications for synthetic genes and other large modified DNA and RNA constructs including non-coding RNAs.

Keywords: (TL)BNA; (TL)DNA; (TL)LNA; (TL)PNA; (TL)RNA; (TL)quadruplexes; 1,2,3-triazoles; backbone modifications; click chemistry; clickable nucleosides and nucleotides; non-coding RNA; synthetic genes; triazole-linkage; triazole-modified oligonucleotides.

Figure 1

Diagram presenting the RNA world.

Figure 2

The comparison of the natural internucleotide linkage with a 1,4- or 1,5-disubstituted 1,2,3-triazole linker.

Figure 3

Triazole DNA template.

Figure 4

Thymidine dinucleoside analogues with imidazole and triazole modified backbones.

Figure 5

N-3 or C-5 branched nucleoside dimers containing a 1,2,3-triazolyl linkage.

Scheme 1

One of the first examples of AZT dimer analogues obtained by CuAAC.

Scheme 2

Synthesis of non-natural dinucleotides and trinucleotide.

Scheme 3

Schematic template-mediated click-ligation of two oligonucleotides.

Scheme 4

Cyclization and bicyclization of oligonucleotides.

Scheme 5

Illustrative depiction of DNA functionalization using click chemistry. R–N₃ any azide-molecule, dU^∗TP is a uridine derivative modified with a terminal alkyne functionality.

Figure 6

1,4- and 1,5-bisnucleosides 1,2,3-triazole derivatives of thymidine and adenosine.

Scheme 6

Synthesis example of a derivative containing the octadiynyl analogue of dU with AZT.

Scheme 7

Different conditions for performing the CuAAC reaction.

Scheme 8

Solid-phase synthesis of 10-mer ^TLDNA.

Figure 7

Phosphoramidite triazole-linked dimers T–T.

Scheme 9

Synthesis and polymerase chain reaction amplification of DNA strands containing an unnatural triazole linkage.

Scheme 10

Alkynyl phosphonate DNA: a versatile clickable backbone for biological applications.

Scheme 11

DNA–RNA hybrids obtained in CuAAC reaction.

Scheme 12

RNA synthesis using phosphoramidite chemistry in the presence of free azide moiety at C2’ position and structure of MSNT.

Scheme 13

Synthesis of triazole-linked r(U_TRA) dimer.

Scheme 14

Synthesis of triazole-linked C_TRU dimer based on a PNA-type scaffold.

Figure 8

mRNA m⁷G 5′-cap clickable analogues.

Scheme 15

The mechanism of preparing sgRNA by click chemistry.

Figure 9

Examples of clickable monomers for LNAs and BNAs synthesis.

Scheme 16

Synthesis of triazole-linked LNA-dimers using Cu(I)-catalyzed click reaction.

Figure 10

Triazole-linked DNA and LNA backbones.

Figure 11

Structure of PNA linked with triazole moiety.

Scheme 17

Illustrative depiction of the use of click chemistry in G-quadruplexes.