Synthesis and Biophysical Studies of N2′-Functionalized 2′-Amino-α-L-LNA

Kumar, Shailendra; Madsen, Andreas Stahl; Wengel, Jesper; Hrdlicka, Patrick J.

doi:10.1080/15257770701538841

Cited by 4 publications

(2 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Appended functional entities were anticipated to be positioned in the major groove of nucleic acid duplexes . However, initial studies with N2′-pyrene-functionalized 2′-amino-α-L-LNA suggest that the conjugated functional entity is directed toward the duplex core instead. , This has already resulted in the development of promising tools for DNA targeting, detection of single nucleotide polymorphisms, and nucleic acid structural engineering…”

Section: Introductionmentioning

confidence: 99%

Functionalized 2′-Amino-α-L-LNA: Directed Positioning of Intercalators for DNA Targeting

et al. 2008

Self Cite

View full text Add to dashboard Cite

Chemically modified oligonucleotides are increasingly applied in nucleic acid based therapeutics and diagnostics. LNA (Locked Nucleic Acid) and its diastereomer α-L-LNA are two promising examples hereof that exhibit increased thermal and enzymatic stability. Herein, the synthesis, biophysical characterization and molecular modeling of N2′-functionalized 2′-amino-α-L-LNA is described. Chemoselective N2′-functionalization of protected amino alcohol 1 followed by phosphitylation afforded a structurally varied set of target phosphoramidites, which were incorporated into oligodeoxyribonucleotides. Incorporation of pyrene-functionalized building blocks such as 2′-N-(pyren-1-yl)carbonyl-2′-amino-α-L-LNA (monomer X) led to extraordinary increases in thermal affinity of up to +19.5 °C per modification against DNA targets in particular. In contrast, incorporation of building blocks with small non-aromatic N2′-functionalities such as 2′-N-acetyl-2′-amino-α-L-LNA (monomer V) had detrimental effects on thermal affinity toward DNA/RNA complements with decreases of as much as −16.5 °C per modification. Extensive thermal DNA selectivity, favorable entropic contributions upon duplex formation, hybridization-induced bathochromic shifts of pyrene absorption maxima and increases of circular dichroism signals, and molecular modeling studies suggest that pyrene functionalized 2′-amino-α-L-LNA monomers W-Y having short linkers between the bicyclic skeleton and the pyrene moiety, allow high-affinity hybridization with DNA complements and precise positioning of intercalators in nucleic acid duplexes. This rigorous positional control has been utilized for the development probes for emerging therapeutic and diagnostic applications focusing on DNA-targeting.

show abstract

Section: Introductionmentioning

confidence: 99%

Functionalized 2′-Amino-α-L-LNA: Directed Positioning of Intercalators for DNA Targeting

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…As a result of our continued efforts to explore locked nucleic acids (LNA), , α-L-LNA and their 2′-amino analogues , in nucleic acid based therapeutics, diagnostics, and nanomaterial engineering, we have recently investigated different pyrene-functionalized derivatives thereof , including pyrene-functionalized 2′-amino-α-L-LNA monomers . Incorporation of the latter type of monomers into ONs results in extensive duplex stabilization presumably as a consequence of precise positional control of intercalators in the duplex core.…”

Section: Introductionmentioning

confidence: 99%

Nucleic Acid Structural Engineering Using Pyrene-Functionalized 2′-Amino-α-L-LNA Monomers and Abasic Sites

et al. 2008

Self Cite

View full text Add to dashboard Cite

Oligonucleotides (ONs) modified with a 2'-N-(pyren-1-yl)acetyl-2'-amino-alpha-L-LNA thymine monomer Y flanked on the 3'-side by an abasic site Phi (i.e., YPhi-unit) exhibit unprecedented increases in thermal affinity (DeltaT(m) values) toward target strands containing abasic sites (DeltaT(m) per YPhi unit >+33.0 degrees C in 9-mer duplexes relative to unmodified ONs). Biophysical studies along with force field calculations suggest that the conformationally locked 2-oxo-5-azabicyclo[2.2.1]heptane skeleton of monomer Y, in concert with the short rigid acetyl linker, efficiently forces the thymine and pyrene moieties to adopt an interplanar distance of approximately 3.4 A. This precisely positions the pyrene moiety in the duplex core void formed by abasic sites (Phi:Phi pair) for optimal pi-pi overlap. Duplexes with multiple YPhi: APhi units separated by one base pair are tolerated extraordinarily well, as exemplified by a 13-mer duplex containing four separated YPhi: APhi units (8 abasic sites distributed over 13 "base pairs"), which exhibit a thermal denaturation temperature of 60.5 degrees C. The YPhi probes display up to 16-fold increases in fluorescence intensity at 380 nm upon hybridization with abasic target strands, whereby self-assembly of these complex architectures can be easily monitored. This study underlines the potential of N2'-functionalized 2'-amino-alpha-L-LNA as building blocks in nucleic acid based diagnostics and nanomaterial engineering.

show abstract

Optimized synthesis of LNA uracil nucleosides

Kumar

Sharma

et al. 2008

Tetrahedron Letters

View full text Add to dashboard Cite

Synthesis and Biophysical Studies of N2′-Functionalized 2′-Amino-α-L-LNA

Cited by 4 publications

References 6 publications

Functionalized 2′-Amino-α-L-LNA: Directed Positioning of Intercalators for DNA Targeting

Functionalized 2′-Amino-α-L-LNA: Directed Positioning of Intercalators for DNA Targeting

Nucleic Acid Structural Engineering Using Pyrene-Functionalized 2′-Amino-α-L-LNA Monomers and Abasic Sites

Optimized synthesis of LNA uracil nucleosides

Contact Info

Product

Resources

About