title: Syntheses and structure-activity relationships of nonnatural beta-C-nucleoside 5'-triphosphates bearing an aromatic nucleobase with phenolic hydroxy groups: inhibitory activities against DNA polymerases.
abstract: Five nonnatural beta-C-nucleoside 5'-triphosphates bearing a 3,4-dihydroxyphenyl (1TP), a 2-hydroxyphenyl (2TP), a 3-hydroxyphenyl (3TP), a 4-hydroxyphenyl (4TP), or a phenyl (5TP) group were synthesized, and their structure-activity relationships were examined for a series of DNA polymerase reactions in vitro under typical polymerase chain reaction conditions. We found that the 5'-triphosphates (1TP-5TP) are not incorporated into DNA strands but inhibit the DNA polymerase reactions in the presence of natural nucleoside 5'-triphosphates (dNTPs). 1TP having two phenolic hydroxy groups at the nucleobase moiety showed the most potent inhibitory effect against DNA synthesis by Ex Taq polymerase (IC(50) = 30 microM). The competition assay indicated that 1TP and dNTPs are most likely to affect DNA polymerase reactions competitively. This finding may raise the appealing possibility that artificial nucleoside 5'-triphosphates having phenolic hydroxy groups could exhibit potent inhibitory activity against DNA-directed enzymatic reactions.
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Saeko
authors.initials: S
authors.lastname: Aketani
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Kaneyoshi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Ishihama
authors.forename: Honghua
authors.initials: H
authors.lastname: Cao
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tengeiji
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hiraoka
authors.forename: Motoo
authors.initials: M
authors.lastname: Shiro
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Shionoya
mesh_terms: D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D019384:Nucleic Acid Synthesis Inhibitors; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry; D016133:Polymerase Chain Reaction; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D009705:Nucleosides; D010755:Organophosphates; D010636:Phenols; D004259:DNA-Directed DNA Polymerase