Issue 14, 2016

Fast and efficient synthesis of Zorro-LNA type 3′-5′-5′-3′ oligonucleotide conjugates via parallel in situ stepwise conjugation

Abstract

Zorro-LNA is a new class of therapeutic anti-gene oligonucleotides (ONs) capable of invading supercoiled DNA. The synthesis of single stranded Zorro-LNA is typically complex and laborious, requiring reverse phosphoramidites and a chemical linker connecting the two separate ON arms. Here, a simplified synthesis strategy based on ‘click chemistry’ is presented with a high potential for screening Zorro-LNA ONs directed against new anti-gene targets. Four different Zorro type 3′-5′ 5′-3′ constructs were synthesized via parallel in situ Cu(I) [3 + 2] catalysed cycloaddition. They were prepared from commercially obtained ONs functionalized on solid support (one ON with the azide and the other ON with the activated triple bond linker N-propynoylamino)-p-toluic acid (PATA)) and after cleavage from resin, they were conjugated in solution. Our report shows the benefit of combining different approaches when developing anti-gene ONs, (1) the ability for rapid and robust screening of potential targets and (2) refining the hits with more anti-gene optimized constructs. We present as well the first report showing double-strand invasion (DSI) efficiency of two combined Zorro-LNAs.

Graphical abstract: Fast and efficient synthesis of Zorro-LNA type 3′-5′-5′-3′ oligonucleotide conjugates via parallel in situ stepwise conjugation

Supplementary files

Article information

Article type
Paper
Submitted
26 Jan 2016
Accepted
10 Mar 2016
First published
11 Mar 2016

Org. Biomol. Chem., 2016,14, 3584-3590

Fast and efficient synthesis of Zorro-LNA type 3′-5′-5′-3′ oligonucleotide conjugates via parallel in situ stepwise conjugation

O. I. Gissberg, M. Jezowska, E. M. Zaghloul, N. I. Bungsu, R. Strömberg, C. I. E. Smith, K. E. Lundin and M. Honcharenko, Org. Biomol. Chem., 2016, 14, 3584 DOI: 10.1039/C6OB00211K

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