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

• Published in: Organic & biomolecular chemistry 2019-01, Vol.17 (2), p.29-31
• Main Authors: Vichier-Guerre, Sophie, Dugué, Laurence, Pochet, Sylvie
• Format: Article
• Language: English
• Subjects: Adenine; Aromatic compounds; Bearing; Calf thymus; Chemical Sciences; Deoxyribonucleic acid; DNA; DNA nucleotidylexotransferase; DNA polymerase; DNA-directed DNA polymerase; Imidazole; NMR; Nuclear magnetic resonance; Nucleotides; Organic chemistry; Polymerization; Substrates
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c8ob02464b

We developed a versatile access to a series of 4-substituted imidazole 2′-deoxynucleoside triphosphate bearing functionalized phenyl or pyrimidinyl rings. 4-Iodo-1 H -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 ( V max / K M ) 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. A modular strategy for the preparation of 2′-deoxyribonucleoside 5′-triphosphates containing 4-arylimidazoles was elaborated. The new DNA building blocks were substrates of DNA polymerases.