Synthesis, nucleic acid hybridization properties and molecular modelling studies of conformationally restricted 3'-O,4' -C-methylene-linked a-L-ribonucleotides

Andreas Stahl Madsen, Patrick J. Hrdlicka, Santhosh T. Kumar, Jesper Wengel

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Nucleotides with conformationally restricted carbohydrate rings such as locked nucleic acid (LNA), α-L-LNA or 2′,5′-linked 3′-O,4′-C-methyleribonucleotides exhibit significant potential as building blocks for antigene and antisense strategies. 2′,5′-Linked α-l-ribo configured monomer X (termed α-L-ONA) was designed as a potential structural mimic of α-L-LNA. The corresponding phosphoramidite building block of monomer X was obtained in five steps (10% overall yield) from the easily obtainable thymine derivative 1. Incorporation of monomer X into oligodeoxyribonucleotides (ONs) results in dramatically decreased thermal stabilities with DNA/RNA complements (ΔTm/mod = −11.5 to −17.0 °C) compared to unmodified reference ONs. Less pronounced decreases (ΔTm/mod = −4.5 to −8.5 °C) are observed when monomer X is incorporated into triplex forming ONs and targeted against double-stranded DNA (parallel orientation, pyrimidine motif). This biophysical data, together with modelling studies, suggest that 2′,5′-linked α-L-ONA is a poor structural mimic of α-L-LNA.

OriginalsprogEngelsk
TidsskriftCarbohydrate Research
Vol/bind341
Udgave nummer10
Sider (fra-til)1398-1407
ISSN0008-6215
DOI
StatusUdgivet - 2006

Fingeraftryk

Ribonucleotides
Molecular modeling
Nucleic Acids
Oligodeoxyribonucleotides
Monomers
Thymine
DNA
Thermodynamic stability
Nucleotides
Carbohydrates
RNA
Derivatives
locked nucleic acid

Citer dette

@article{7e4b3e90e10811db9628000ea68e967b,
title = "Synthesis, nucleic acid hybridization properties and molecular modelling studies of conformationally restricted 3'-O,4' -C-methylene-linked a-L-ribonucleotides",
abstract = "Nucleotides with conformationally restricted carbohydrate rings such as locked nucleic acid (LNA), α-L-LNA or 2′,5′-linked 3′-O,4′-C-methyleribonucleotides exhibit significant potential as building blocks for antigene and antisense strategies. 2′,5′-Linked α-l-ribo configured monomer X (termed α-L-ONA) was designed as a potential structural mimic of α-L-LNA. The corresponding phosphoramidite building block of monomer X was obtained in five steps (10{\%} overall yield) from the easily obtainable thymine derivative 1. Incorporation of monomer X into oligodeoxyribonucleotides (ONs) results in dramatically decreased thermal stabilities with DNA/RNA complements (ΔTm/mod = −11.5 to −17.0 °C) compared to unmodified reference ONs. Less pronounced decreases (ΔTm/mod = −4.5 to −8.5 °C) are observed when monomer X is incorporated into triplex forming ONs and targeted against double-stranded DNA (parallel orientation, pyrimidine motif). This biophysical data, together with modelling studies, suggest that 2′,5′-linked α-L-ONA is a poor structural mimic of α-L-LNA.",
keywords = "LNA, 2',5'-linked nucleic acids, conformationally restricted nucleosides, oligonucleotides, oxetane",
author = "Madsen, {Andreas Stahl} and Hrdlicka, {Patrick J.} and Kumar, {Santhosh T.} and Jesper Wengel",
year = "2006",
doi = "10.1016/j.carres.2006.04.010",
language = "English",
volume = "341",
pages = "1398--1407",
journal = "Carbohydrate Research",
issn = "0008-6215",
publisher = "Pergamon Press",
number = "10",

}

Synthesis, nucleic acid hybridization properties and molecular modelling studies of conformationally restricted 3'-O,4' -C-methylene-linked a-L-ribonucleotides. / Madsen, Andreas Stahl; Hrdlicka, Patrick J.; Kumar, Santhosh T.; Wengel, Jesper.

I: Carbohydrate Research, Bind 341, Nr. 10, 2006, s. 1398-1407.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Synthesis, nucleic acid hybridization properties and molecular modelling studies of conformationally restricted 3'-O,4' -C-methylene-linked a-L-ribonucleotides

AU - Madsen, Andreas Stahl

AU - Hrdlicka, Patrick J.

AU - Kumar, Santhosh T.

AU - Wengel, Jesper

PY - 2006

Y1 - 2006

N2 - Nucleotides with conformationally restricted carbohydrate rings such as locked nucleic acid (LNA), α-L-LNA or 2′,5′-linked 3′-O,4′-C-methyleribonucleotides exhibit significant potential as building blocks for antigene and antisense strategies. 2′,5′-Linked α-l-ribo configured monomer X (termed α-L-ONA) was designed as a potential structural mimic of α-L-LNA. The corresponding phosphoramidite building block of monomer X was obtained in five steps (10% overall yield) from the easily obtainable thymine derivative 1. Incorporation of monomer X into oligodeoxyribonucleotides (ONs) results in dramatically decreased thermal stabilities with DNA/RNA complements (ΔTm/mod = −11.5 to −17.0 °C) compared to unmodified reference ONs. Less pronounced decreases (ΔTm/mod = −4.5 to −8.5 °C) are observed when monomer X is incorporated into triplex forming ONs and targeted against double-stranded DNA (parallel orientation, pyrimidine motif). This biophysical data, together with modelling studies, suggest that 2′,5′-linked α-L-ONA is a poor structural mimic of α-L-LNA.

AB - Nucleotides with conformationally restricted carbohydrate rings such as locked nucleic acid (LNA), α-L-LNA or 2′,5′-linked 3′-O,4′-C-methyleribonucleotides exhibit significant potential as building blocks for antigene and antisense strategies. 2′,5′-Linked α-l-ribo configured monomer X (termed α-L-ONA) was designed as a potential structural mimic of α-L-LNA. The corresponding phosphoramidite building block of monomer X was obtained in five steps (10% overall yield) from the easily obtainable thymine derivative 1. Incorporation of monomer X into oligodeoxyribonucleotides (ONs) results in dramatically decreased thermal stabilities with DNA/RNA complements (ΔTm/mod = −11.5 to −17.0 °C) compared to unmodified reference ONs. Less pronounced decreases (ΔTm/mod = −4.5 to −8.5 °C) are observed when monomer X is incorporated into triplex forming ONs and targeted against double-stranded DNA (parallel orientation, pyrimidine motif). This biophysical data, together with modelling studies, suggest that 2′,5′-linked α-L-ONA is a poor structural mimic of α-L-LNA.

KW - LNA

KW - 2',5'-linked nucleic acids

KW - conformationally restricted nucleosides

KW - oligonucleotides

KW - oxetane

U2 - 10.1016/j.carres.2006.04.010

DO - 10.1016/j.carres.2006.04.010

M3 - Journal article

VL - 341

SP - 1398

EP - 1407

JO - Carbohydrate Research

JF - Carbohydrate Research

SN - 0008-6215

IS - 10

ER -