Mono- and diaminated 2'-amino-LNA monomers were synthesized and introduced into oligonucleotides. Each modification imparts significant stabilization of nucleic acid duplexes and triplexes, excellent sequence selectivity, and significant nuclease resistance. Molecular modeling suggested that structural stabilization occurs via intrastrand electrostatic attraction between the protonated amino groups of the aminated 2'-amino-LNA monomers and the host oligonucleotide backbone.
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Polyamine-Functionalized 2'-Amino-LNA in Oligonucleotides: Facile Synthesis of New Monomers and High-Affinity Binding towards ssDNA and dsDNA.
Chemistry
January 2021
Biomolecular Nanoscale Engineering Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.
Attachment of cationic moieties to oligonucleotides (ONs) promises not only to increase the binding affinity of antisense ONs by reducing charge repulsion between the two negatively charged strands of a duplex, but also to augment their in vivo stability against nucleases. In this study, polyamine functionality was introduced into ONs by means of 2'-amino-LNA scaffolds. The resulting ONs exhibited efficient binding towards ssDNA, ssRNA and dsDNA targets, and the 2'-amino-LNA analogue carrying a triaminated linker showed the most pronounced duplex- and triplex-stabilizing effect.
View Article and Find Full Text PDFSynthesis of Oligonucleotides Containing 2'--alkylaminocarbonyl-2'-amino-LNA (2'-urea-LNA) Moieties Using Post-Synthetic Modification Strategy.
Molecules
January 2020
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Nishihama, Yamashiro-cho, Tokushima 770-8514, Japan.
The post-synthetic modification of an oligonucleotide is a powerful strategy for the synthesis of various analogs of the oligonucleotide, aiming to achieve the desired functions. In this study, we synthesized the thymidine phosphoramidite of 2'--pentafluorophenoxycarbonyl-2'-amino-LNA, which was introduced into oligonucleotides. Oligonucleotides containing a 2'--pentafluorophenoxycarbonyl-2'-amino-LNA unit could be isolated under ultra-mild deprotection conditions (50 mM KCO in MeOH at room temperature for 4 h).
View Article and Find Full Text PDFOligonucleotides Containing Aminated 2'-Amino-LNA Nucleotides: Synthesis and Strong Binding to Complementary DNA and RNA.
Bioconjug Chem
April 2017
Department of Chemistry, Biomolecular Nanoscale Engineering Center, University of Copenhagen, Thorvaldsensvej 40, Frederiksberg 1871, Denmark.
Mono- and diaminated 2'-amino-LNA monomers were synthesized and introduced into oligonucleotides. Each modification imparts significant stabilization of nucleic acid duplexes and triplexes, excellent sequence selectivity, and significant nuclease resistance. Molecular modeling suggested that structural stabilization occurs via intrastrand electrostatic attraction between the protonated amino groups of the aminated 2'-amino-LNA monomers and the host oligonucleotide backbone.
View Article and Find Full Text PDFEffective modulation of DNA duplex stability by reversible transition metal complex formation in the minor groove.
J Am Chem Soc
August 2007
Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, Odense M, Denmark.
Herein we describe the reversible changing of DNA duplex thermal stability by exploiting transition metal complexation phenomena. A terpyridine ligand was conjugated to the N2'-atoms of 2'-amino-2'-deoxyuridine and its locked counterpart 2'-amino-LNA, and these metal-complexing monomers were incorporated into oligodeoxyribonucleotides. Upon addition of varying amounts of transition metal ions, the thermal stability of DNA duplexes containing these terpyridine-functionalized units in different constitutions was affected to different degrees (DeltaTm values = -15.
View Article and Find Full Text PDFChemical and structural implications of 1',2'- versus 2',4'- conformational constraints in the sugar moiety of modified thymine nucleosides.
J Org Chem
June 2007
Department of Bioorganic Chemistry, Box 581, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden.
In order to understand how the chemical nature of the conformational constraint of the sugar moiety in ON/RNA(DNA) dictates the duplex structure and reactivity, we have determined molecular structures and dynamics of the conformationally constrained 1',2'-azetidine- and 1',2'-oxetane-fused thymidines, as well as their 2',4'-fused thymine (T) counterparts such as LNA-T, 2'-amino LNA-T, ENA-T, and aza-ENA-T by NMR, ab initio (HF/6-31G** and B3LYP/6-31++G**), and molecular dynamics simulations (2 ns in the explicit aqueous medium). It has been found that, depending upon whether the modification leads to a bicyclic 1',2'-fused or a tricyclic 2',4'-fused system, they fall into two distinct categories characterized by their respective internal dynamics of the glycosidic and the backbone torsions as well as by characteristic North-East type sugar conformation (P = 37 degrees +/- 27 degrees , phi(m) = 25 degrees +/- 18 degrees ) of the 1',2'-fused systems, and (ii) pure North type (P = 19 degrees +/- 8 degrees , phi(m) = 48 degrees +/- 4 degrees ) for the 2',4'-fused nucleosides. Each group has different conformational hyperspace accessible, despite the overall similarity of the North-type conformational constraints imposed by the 1',2'- or 2',4'-linked modification.
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