Xanthine Base Pairing with 2‐Aminoadenine and Canonical Bases in Purine Tracts of Watson‐Crick DNA: Impact of Purine‐, 7‐Deazapurine‐ and 8‐Aza‐7‐deazapurine Heterocyclic Skeletons on Duplex Stability

The impact of purine, 7‐deazapurine and 8‐aza‐7‐deazapurine heterocyclic skeletons on the stability of the xanthine‐2‐aminoadenine base pair is reported. Beyond that, base‐pairing of xanthine nucleosides opposite canonical nucleobases is studied. To this end, a building block of 8‐aza‐7‐deaza‐2′‐deoxyxanthosine was prepared using 8‐aza‐7‐deaza‐2′‐deoxyguanosine as starting material. A simplified synthesis for large‐scale production is presented for the phosphoramidite of 2‐amino‐7‐bromo‐7‐deaza‐2′‐deoxyadenosine (2‐NH 2 Br 7 c 7 z 8 A d ). Hybridization of oligonucleotides gave duplexes containing single or multiple incorporations of xanthine‐2‐aminoadenine base pairs with different combinations of nucleobases. From melting curves and T m values, it became apparent that the most stable duplexes contained base pairs of 2‐NH 2 Br 7 c 7 z 8 A d with xanthine nucleosides. Under these, the 7‐deazaxanthine‐2‐NH 2 Br 7 c 7 z 8 A d base pair reached the stability of dT‐2‐NH 2 Br 7 c 7 z 8 A d and dG‐dC pairs. 7‐Deazaxanthine located opposite 2‐aminoadenine residues resulted in higher duplex stability compared to xanthine or 8‐aza‐7‐deazaxanthine. For 2‐aminoadenine residues, the base pair stability followed the order 2‐amino‐8‐aza‐7‐bromo‐7‐deazaadenine > 2‐aminoadenine > 7‐deazaadenine. The impact of p K values became obvious from the increased stability of xanthine‐2‐aminoadenine pairs by decreasing the pH. Single incorporations of xanthine residues opposite canonical nucleobases displayed inhomogeneous pairing properties. Tracts of three xanthine residues in front of adenine and guanine furnished stable duplexes, whereas with cytosine and thymine, duplex formation was hindered.