title: Structure/affinity studies in the bicyclo-DNA series: Synthesis and properties of oligonucleotides containing bc(en)-T and iso-tricyclo-T nucleosides.
abstract: We present the synthesis of the two novel nucleosides iso-tc-T and bc(en)-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 bc(en)-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 T m data of single modifications with nucleosides of the bicyclo-/tricyclo-DNA platform within deoxyoligonucleotides are not predictive for the stability of fully modified oligonucleotides.
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland.
authors.forename: Branislav
authors.initials: B
authors.lastname: Dugovic
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Leumann
keywords: DNA/RNA affinity; X-ray structures; nucleic acids; nucleosides; oligonucleotide therapy; oligonucleotides