2′-Deoxyribonucleoside 5′-triphosphates bearing 4-phenyl and 4-pyrimidinyl imidazoles as DNA polymerase substrates?

Organic & Biomolecular Chemistry Pub Date: 2018-12-04 DOI: 10.1039/C8OB02464B

Abstract

We developed a versatile access to a series of 4-substituted imidazole 2′-deoxynucleoside triphosphate bearing functionalized phenyl or pyrimidinyl rings. 4-Iodo-1H-imidazole was enzymatically converted into the corresponding 2′-deoxynucleoside, which was then chemically derived into its 5′-triphosphate, followed by 4-arylation via Suzuki–Miyaura coupling using (hetero)arylboronic acids. Both KF (exo-) and Deep Vent (exo-) DNA polymerases incorporated these modified nucleotides in primer-extension assays, adenine being the preferred pairing partner in the template. The 4-(3-aminophenyl)imidazole derivative (3APh) was the most efficiently inserted opposite A by KF (exo-) with only a 37-fold lower efficiency (Vmax/KM) than that of the correct dTTP. No further extension occurred after the incorporation of a single aryl-imidazole nucleotide. Interestingly, the aryl-imidazole dNTPs were found to undergo successive incorporation by calf thymus terminal deoxynucleotidyl transferase with different tailing efficiencies among this series and with a marked preference for 2APyr polymerization.

Graphical abstract: 2′-Deoxyribonucleoside 5′-triphosphates bearing 4-phenyl and 4-pyrimidinyl imidazoles as DNA polymerase substrates
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