Nucleic acid structural engineering using pyrene-functionalized 2'-amino-alpha-L-LNA monomers and abasic sites

The Journal of Organic Chemistry
T Santhosh KumarPatrick J Hrdlicka

Abstract

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, whereb...Continue Reading

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Citations

Mar 20, 2012·Chemical Reviews·Yin Nah Teo, Eric T Kool
Aug 11, 2011·The Journal of Organic Chemistry·Saswata KarmakarPatrick J Hrdlicka
Nov 18, 2011·The Journal of Organic Chemistry·Sujay P Sau, Patrick J Hrdlicka
Dec 26, 2008·The Journal of Organic Chemistry·T Santhosh KumarPatrick J Hrdlicka
Apr 20, 2010·Organic & Biomolecular Chemistry·Sujay P SauPatrick J Hrdlicka
Jun 8, 2010·Chemical Communications : Chem Comm·Michael E ØstergaardPatrick J Hrdlicka
Apr 10, 2009·Bioorganic & Medicinal Chemistry Letters·T Santhosh KumarPatrick J Hrdlicka
Apr 27, 2010·Chemical Society Reviews·Erik SchwartzAlan E Rowan
Feb 18, 2011·Chemistry : a European Journal·Michael E ØstergaardPatrick J Hrdlicka
Apr 5, 2020·International Journal of Molecular Sciences·Prithi RaguramanRakesh N Veedu
Jun 21, 2012·Chemistry : a European Journal·Tadao TakadaKazushige Yamana
May 3, 2013·Chemical Communications : Chem Comm·Larysa I MarkovaRobert Häner
Jan 30, 2010·Chemical Society Reviews·Vladimir L MalinovskiiRobert Häner
Feb 5, 2015·Angewandte Chemie·Christian B WinigerRobert Häner
Sep 18, 2010·Journal of the American Chemical Society·Michael E ØstergaardPatrick J Hrdlicka

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