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Molecules 2015, 20(3), 4020-4041; doi:10.3390/molecules20034020

Hybridisation Potential of 1',3'-Di-O-methylaltropyranoside Nucleic Acids

Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven BE-3000, Belgium
These authors contributed equally to this work.
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Author to whom correspondence should be addressed.
Academic Editor: Mahesh K. Lakshman
Received: 22 January 2015 / Revised: 16 February 2015 / Accepted: 24 February 2015 / Published: 3 March 2015
(This article belongs to the Special Issue Nucleoside Modifications)
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Abstract

In further study of our series of six-membered ring-containing nucleic acids, different 1',3'-di-O-methyl altropyranoside nucleoside analogs (DMANA) were synthesized comprising all four base moieties, adenine, cytosine, uracil and guanine. Following assembly into oligonucleotides (ONs), their affinity for natural oligonucleotides was evaluated by thermal denaturation of the respective duplexes. Data were compared with results obtained previously for both anhydrohexitol (HNAs) and 3'-O-methylated altrohexitol modified ONs (MANAs). We hereby demonstrate that ONs modified with DMANA monomers, unlike some of our previously described analogues with constrained 6-membered hexitol rings, did not improve thermodynamic stability of dsRNA complexes, most probably in view of an energetic penalty when forced in the required 1C4 pairing conformation. Overall, a single incorporation was more or less tolerated or even positive for the adenine congener, but incorporation of a second modification afforded a slight destabilization (except for A), while a fully modified sequence displayed a thermal stability of −0.3 °C per modification. The selectivity of pairing remained very high, and the new modification upon incorporation into a DNA strand, strongly destabilized the corresponding DNA duplexes. Unfortunately, this new modification does not bring any advantage to be further evaluated for antisense or siRNA applications. View Full-Text
Keywords: modified oligonucleotides; hexitol nucleic acids; pairing behaviour; hybridisation; constrained oligonucleotides modified oligonucleotides; hexitol nucleic acids; pairing behaviour; hybridisation; constrained oligonucleotides
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Venkatesham, A.; Kachare, D.; Schepers, G.; Rozenski, J.; Froeyen, M.; Van Aerschot, A. Hybridisation Potential of 1',3'-Di-O-methylaltropyranoside Nucleic Acids. Molecules 2015, 20, 4020-4041.

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