Inhibitory effect of dipeptide alcohol derivatives containing mercapto group on eukaryotic DNA polymerase alpha.
We reported previously that a novel dipeptide alcohol, L-homoserylaminoethanol (Hse-Gly-ol), is a selective inhibitor of eukaryotic DNA polymerase epsilon (pol epsilon). The discovery suggests that the dipeptide structure could be a chemical frame for a DNA polymerase inhibitor. Therefore, we chemically synthesized 14 different species of dipeptide alcohols and their derivatives, and tested this inhibitory capability. The mercapto group in the dipeptide alcohol was found to be important, and compound 4 (L-cysteinylaminoethanol, Cys-Gly-ol) was the strongest pol alpha inhibitor. Compound 4 did not influence the activities of other replicative DNA polymerases such as delta and epsilon, and had no effect on the activities of prokaryotic DNA polymerases, nor DNA metabolic enzymes such as human immunodeficiency virus type-1 reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. The inhibitory effect of compound 4 on pol alpha was dose-dependent, and 50% inhibition was observed at a concentration of 14.8 microM. Compound 4-induced inhibition of pol alpha activity was non-competitive with both the DNA template-primer and the nucleotide substrate. The relationships between the structures of dipeptide alcohol and the inhibition of eukaryotic DNA polymerases are discussed.
Kato
Ikuo
I
Yanaihara Institute Inc., Awakura, Fujinomiya, Shizuoka 418-0011, Japan.
Kuriyama
Isoko
I
Asano
Naoki
N
Ikeda
Kyoko
K
Yoshida
Hiromi
H
Mizushina
Yoshiyuki
Y
D000605:Amino Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004247:DNA / Q000378:metabolism; D004253:DNA Nucleotidylexotransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000737:chemistry; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
D000605:Amino Alcohols; D004151:Dipeptides; D007527:Isoenzymes; D013438:Sulfhydryl Compounds; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004253:DNA Nucleotidylexotransferase; D019098:Telomerase; D004256:DNA Polymerase I; D004264:DNA Topoisomerases, Type I