Isoguanine (2-Hydroxyadenine) and 2-Aminoadenine Nucleosides with an 8-Aza-7-deazapurine Skeleton: Synthesis, Functionalization with Fluorescent and Clickable Side Chains, and Impact of 7-Substituents on Physical Properties.

Abstract

7-Functionalized 8-aza-7-deaza-2'-deoxyisoguanine and 8-aza-7-deaza-2-aminoadenine 2'-deoxyribonucleosides decorated with fluorescent pyrene or benzofuran sensor tags or clickable side chains with terminal triple bonds were synthesized. 8-Aza-7-deaza-7-iodo-2-amino-2'-deoxyadenosine was used as the central intermediate and was accessible by an improved two-step glycosylation/amination protocol. Functionalization of position-7 was performed either on 8-aza-7-deaza-7-iodo-2-amino-2'-deoxyadenosine followed by selective deamination of the 2-amino group or on 7-iodinated 8-aza-7-deaza-2'-deoxyisoguanosine. Sonogashira and Suzuki-Miyaura cross-coupling reactions were employed for this purpose. Octadiynyl side chains were selected as linkers for click reactions with azido pyrenes. KTaut values calculated from H2O/dioxane mixtures revealed that side chains have a significant influence on the tautomeric equilibrium. Photophysical properties (fluorescence, solvatochromism, and quantum yields) of the new 8-aza-7-deazapurine nucleosides with fluorescent side chains were determined. Remarkably, a strong excimer fluorescence in H2O was observed for pyrene dye conjugates of 8-aza-7-deazaisoguanine and 2-aminoadenine nucleosides with a long linker. In other solvents including methanol, excimer fluorescence was negligible. The 2-aminoadenine and isoguanine nucleosides with the 8-aza-7-deazapurine skeleton expand the class of nucleosides applicable to fluorescence detection with respect to diagnostic and therapeutic purposes.