Structure/affinity studies in the bicyclo-DNA series: Synthesis and properties of oligonucleotides containing bcen-T and iso-tricyclo-T nucleosides

Dugovic, Branislav; Wagner, Michael; Leumann, Christian J. (2014). Structure/affinity studies in the bicyclo-DNA series: Synthesis and properties of oligonucleotides containing bcen-T and iso-tricyclo-T nucleosides. Beilstein journal of organic chemistry, 10, pp. 1840-1847. Beilstein-Institut 10.3762/bjoc.10.194

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We present the synthesis of the two novel nucleosides iso-tc-T and bcen-T, belonging to the bicyclo-/tricyclo-DNA molecular platform. In both modifications the torsion around C6’–C7’ within the carbocyclic ring is planarized by either the presence of a C6’–C7’ double bond or a cyclopropane ring. Structural analysis of these two nucleosides by X-ray analysis reveals a clear preference of torsion angle γ for the gauche orientation with the furanose ring in a near perfect 2’-endo conformation. Both modifications were incorporated into oligodeoxynucleotides and their thermal melting behavior with DNA and RNA as complements was assessed. We found that the iso-tc-T modification was significantly more destabilizing in duplex formation compared to the bcen-T modification. In addition, duplexes with complementary RNA were less stable as compared to duplexes with DNA as complement. A structure/affinity analysis, including the already known bc-T and tc-T modifications, does not lead to a clear correlation of the orientation of torsion angle γ with DNA or RNA affinity. There is, however, some correlation between furanose conformation (N- or S-type) and affinity in the sense that a preference for a 3’-endo like conformation is associated with a preference for RNA as complement. As a general rule it appears that Tm data of single modifications with nucleosides of the bicyclo-/tricyclo-DNA platform within deoxyoligonucleotides are not predictive for the stability of fully modified oligonucleotides.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Dugovic, Branislav and Leumann, Christian

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

1860-5397

Publisher:

Beilstein-Institut

Language:

English

Submitter:

Christian Leumann

Date Deposited:

22 Aug 2014 16:38

Last Modified:

26 Dec 2014 18:42

Publisher DOI:

10.3762/bjoc.10.194

Uncontrolled Keywords:

DNA/RNA affinity, nucleic acids, nucleosides, oligonucleotides, oligonucleotide therapy, X-ray structures

BORIS DOI:

10.7892/boris.57940

URI:

https://boris.unibe.ch/id/eprint/57940

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