The efficient synthesis, antiviral activity, and duplex-stabilizing properties of both isomers of the 2'-fluoro analogue of Northern methanocarbathymidine (N-MCT), 2 and 3, are reported. We show that 2'-F incorporation on the N-MCT scaffold has a strong stabilizing effect on duplex thermal stability.
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http://dx.doi.org/10.1002/anie.201405283 | DOI Listing |
Nucleic Acids Res
December 2021
Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany.
DNA base modifications diversify the genome and are essential players in development. Yet, their influence on DNA physical properties and the ensuing effects on genome metabolism are poorly understood. Here, we focus on the interplay of cytosine modifications and DNA processes.
View Article and Find Full Text PDFNucleic Acids Res
December 2018
Department of Organic and Macromolecular Chemistry, NMR and Structure Analysis Research Group, Ghent University, Gent, Oost-Vlaanderen 9000, Belgium.
Previous investigations of the impact of an imidazole-tethered thymidine in synthetic DNA duplexes, monitored using UV and NMR spectroscopy, revealed a base context dependent increase in thermal stability of these duplexes and a striking correlation with the imidazolium pKa. Unrestrained molecular dynamics (MD) simulations demonstrated the existence of a hydrogen bond between the imidazolium and the Hoogsteen side of a nearby guanosine which, together with electrostatic interactions, form the basis of the so-called pKa-motif responsible for these duplex-stabilizing and pKa-modulating properties. Here, the robustness and utility of this pKa-motif was explored by introducing multiple imidazole-tethered thymidines at different positions on the same dsDNA duplex.
View Article and Find Full Text PDFOrg Biomol Chem
February 2016
Department of Chemistry, Université de Montréal, P.O. Box 6128, Downtown Station, Montréal, QC H3C 3J7, Canada.
The design, synthesis and biophysical evaluation of two highly-constrained tricyclic analogues of locked nucleic acid (LNA), which restrict rotation around the C4'-C5'-exocyclic bond (torsion angle γ) and enhance hydrophobicity in the minor groove and along the major groove, are reported. A structural model that provides insights into the sugar-phosphate backbone conformations required for efficient hybridization to complementary nucleic acids is also presented.
View Article and Find Full Text PDFJ Org Chem
October 2015
Nucleic Acid Center, Department of Physics, Chemistry & Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense, Denmark.
Consecutive incorporations of our previously published thymidine analogue, 5-(1-phenyl-1H-1,2,3-triazol-4-yl)-2'-deoxyuridine monomer W in oligonucleotides, has demonstrated significant duplex-stabilizing properties due to its efficient staking properties in the major groove of DNA:RNA duplexes. The corresponding 2'-deoxycytidine analogue is not as well-accommodated in duplexes, however, due to its clear preference for the ring-flipped coplanar conformation. In our present work, we have used ab initio calculations to design two new building blocks, 5-(5-phenylfuran-2-yl)-2'-deoxycytidine monomer Y and 5-(1-phenyl-1H-pyrazol-3-yl)-2'-deoxycytidine monomer Z, that emulate the conformation of W.
View Article and Find Full Text PDFJ Org Chem
September 2014
Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc. , 2855 Gazelle Court, Carlsbad, California 92010, United States.
We compare the duplex stabilizing properties of 2'-fluorinated nucleic acid analogues with furanose and non-furanose ring systems and dissect the relative contributions of hydration, sugar conformation, and fluorine configuration toward the overall T(m) value. We find that the stabilization imparted by fluorine substitution is additive over that obtained by restricting the conformation of the sugar ring itself. Our studies support further evaluation of fluorinated nucleic acid analogues with non-furanose sugar rings as surrogates of 2'-F RNA for therapeutic antisense applications.
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