Nucleic‐Acid Analogs with Restricted Conformational Flexibility in the Sugar‐Phosphate Backbone (‘Bicyclo‐DNA’). Part 5. Synthesis, Characterization, and Pairing Properties of Oligo‐α‐D‐(bicyclodeoxynucleotides) of the Bases Adenine and Thymine (α‐Bicyclo‐DNA)

Abstract

AbstractA conformational analysis of the (3′S,5′R)‐2′‐deoxy‐3′,5′‐ethano‐α‐D‐ribonucleosides (a‐D‐bicyclodeoxynucleosides) based on the X‐ray analysis of N4‐benzoyl‐α‐D‐(bicyclodeoxycytidine) 6 and on 1H‐NMR analysis of the α‐D‐bicyclodeoxynucleoside derivatives 1‐7 reveals a rigid sugar structure with the furanose units in the l′‐exo/2′‐endo conformation and the secondary OH groups on the carbocyclic ring in the pseudoequatorial orientation. Oligonucleotides consisting of α‐D‐bicyclothymidine and α‐D‐bicyclodeoxyadenosine were successfully synthesized from the corresponding nucleosides by phosphoramidite methodology on a DNA synthesizer. An evaluation of their pairing properties with complementary natural RNA and DNA by means of UV/melting curves and CD spectroscopy show the following characteristics: i) α‐bcd(A10) and α‐bcd(T10) (α = short form of α‐D)efficiently form complexes with complementary natural DNA and RNA. The stability of these hybrids is comparable or slightly lower as those with natural β‐d(A10) or β‐d(T10)( β = short form ofβ‐D). ii) The strand orientation in α‐bicyclo‐DNA/β‐DNA duplexes is parallel as was deduced from UV/melting curves of decamers with nonsymmetric base sequences. iii) CD Spectroscopy shows significant structural differences between α‐bicyclo‐DNA/β‐DNA duplexes compared to α‐DNA/β‐DNA duplexes. Furthermore, α‐bicyclo‐DNA is ca. 100‐fold more resistant to the enzyme snake‐venom phosphodiesterase with respect to β‐DNA and about equally resistant as α‐DNA.