Volume 2009, Issue 8 p. 1153-1162
Full Paper

Screening the Structural Space of Bicyclo-DNA: Synthesis and Thermal Melting Properties of bc4,3-DNA

Andrea Stauffiger

Andrea Stauffiger

Department of Chemistry and Biochemistry, University of Bern Freiestrasse 3, 3012 Bern, Switzerland, Fax: +41-31-631-34-22

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Christian J. Leumann

Christian J. Leumann

Department of Chemistry and Biochemistry, University of Bern Freiestrasse 3, 3012 Bern, Switzerland, Fax: +41-31-631-34-22

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First published: 23 February 2009
Citations: 21

Graphical Abstract

A novel member of the bicyclonucleoside family [4.3.0]bicyclothymidine was synthesized and incorporated into oligodeoxynucleotides. Their pairing properties to complementary DNA and RNA were investigated and found to be similar to that of the known [3.3.0]bicyclo-DNA.

Abstract

In attempts to screen the structural and functional properties of bicyclo-DNA, in which the ribose C(3′) and C(5′) centers are integrated into an additional five-membered carbocyclic ring ([3.3.0]-series) we have now synthesized and investigated a ring enlarged analogue in which C(5′) and C(3′) are spanned by a six-membered carbocyclic ring ([4.3.0]-series). The synthesis of the corresponding bc4,3-T nucleoside 13 was performed in 12 steps by starting from known allyl furanose 1. X-ray analysis of its benzyl protected precursor 12 showed the cyclohexane ring to adopt a chair conformation with the O(5′) substituent in an axial position. The furanose part shows clearly S-type sugar pucker. This nucleoside was converted into the corresponding phosphoramidite building block 15 and incorporated into oligodeoxynucleotides by standard phosphoramidite chemistry. The thermal stabilities of oligonucleotides with single or double incorporations of bc4,3-T residues, paired to complementary DNA or RNA, were found to be similar to those of unmodified oligonucleotides (–2.3 to +0.7 °C per modification) and to those with the known bc-T modifications. We also found that mismatch discrimination in the bc4,3-T series was similar to that of the natural series but less discriminative in comparison to the known bc-T series.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)