Base-Pairing, Tautomerism, and Mismatch Discrimination of 7-Halogenated 7-Deaza-2‘-deoxyisoguanosine: Oligonucleotide Duplexes with Parallel and Antiparallel Chain Orientation

Oligonucleotides containing 2‘-deoxyisoguanosine (1, iGd), 7-deaza-2‘-deoxyisoguanosine (2,
c7iGd), and its 7-halogenated derivatives 3 and 4 were synthesized on solid phase using the phosphoramidite
building blocks 5−7. The hybridization properties of oligonucleotides were studied on duplexes with parallel
and antiparallel chain orientation. It was found that the 7-halogenated nucleoside analogues 3 and 4 enhance
the duplex stability significantly in both parallel (ps) and antiparallel (aps) DNA. Moreover, the halogenated
nucleosides shift the tautomeric keto−enol equilibrium strongly toward the keto form, with KTAUT [keto]/[enol] ≈ 104 coming close to that of 2‘-deoxyguanosine (104−105), while the nonhalogenated 7-deaza-2‘-deoxyisoguanosine 2 shows a KTAUT of around 2000 and the enol concentration of 1 is 10% in aqueous
solution. Consequently, nucleosides 3 and 4 show a much better mismatch discrimination against dT than
compound 1 or 2 in antiparallel as well as in parallel DNA. 3 and 4 are expected to increase the selectivity
of base incorporation opposite to isoCd in the form of triphosphates or in the polymerase-catalyzed reaction
in comparison to 1 or 2.