High-Affinity RNA Targeting by Oligonucleotides Displaying Aromatic Stacking and Amino Groups in the Major Groove. Comparison of Triazoles and Phenyl Substituents

• Published in: Journal of organic chemistry 2014-04, Vol.79 (7), p.2854-2863
• Main Authors: Kumar, Pawan, Hornum, Mick, Nielsen, Lise J, Enderlin, Gérald, Andersen, Nicolai Krog, Len, Christophe, Hervé, Gwénaëlle, Sartori, Guillaume, Nielsen, Poul
• Format: Article
• Language: English
• Subjects: Amines - chemistry; Chemical Sciences; Deoxyuridine - analogs & derivatives; Deoxyuridine - chemistry; DNA - chemistry; Models, Molecular; Molecular Structure; Nucleic Acid Conformation; Oligonucleotides - chemistry; RNA - chemistry; Triazoles - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo4025896

Three 5-modified 2′-deoxyuridine nucleosides were synthesized and incorporated into oligonucleotides and compared with the previously published 5-(1-phenyl-1,2,3-triazol-4-yl)-2′-deoxyuridine monomer W. The introduction of an aminomethyl group on the phenyl group led to monomer X, which was found to thermally stabilize a 9-mer DNA:RNA duplex, presumably through the partial neutralization of the negative charge of the backbone. By also taking advantage of the stacking interactions in the major groove of two or more of the monomer X, an extremely high thermal stability was obtained. A regioisomer of the phenyltriazole substituent, that is the 5-(4-phenyl-1,2,3-triazol-1-yl)-2′-deoxyuridine monomer Y, was found to destabilize the DNA:RNA duplex significantly, but stacking in the major groove compensated for this when two to four monomers were incorporated consecutively. Finally, the 5-phenyl-2′-deoxyuridine monomer Z was incorporated for comparison, and it was found to give a more neutral influence on duplex stability indicating less efficient stacking interactions. The duplexes were investigated by CD spectroscopy and MD simulations.