title: The specific inhibitory effect of demethoxydehydroaltenusin, a derivative of dehydroaltenusin, on mammalian DNA polymerase alpha.
abstract: In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin from the fungus Acremonium sp. was found to be an inhibitor of pol alpha. The present study succeeded in chemically synthesizing dehydroaltenusin, and the compound strongly inhibited calf pol alpha activity and weakly suppressed rat pol beta activity, with IC50 values of 0.68 and 64 microM, respectively. We purified or synthesized various slightly modified derivatives of dehydroaltenusin, and using these, investigated the relationship between chemical structure and the inhibitory effects. These results suggest that the ketone group at the 5'-position in dehydroaltenusin is essential for pol inhibitory activity, and the group at the 5-position is important for the specificity of pol alpha inhibition. Demethoxydehydroaltenusin was found to be the most specific pol alpha inhibitor among the prepared derivatives, and the IC50 values for pols alpha and beta were 0.24 and 89 microM, respectively. This compound did not influence the activities of other replicative pols such as pols delta and epsilon, and also demonstrated no effect on pol alpha activity from another vertebrate, fish and a plant species. Demethoxydehydroaltenusin also had no influence on the other pols and DNA metabolic enzymes tested. Therefore, demethoxydehydroaltenusin is of interest as a mammalian pol alpha-selective inhibitor as a 'chemical knockout agent' in vitro and in vivo.
authors.affiliation: Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Hyogo 651-2180, Japan.
authors.forename: Isoko
authors.initials: I
authors.lastname: Kuriyama
authors.forename: Keishi
authors.initials: K
authors.lastname: Fukudome
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Kouji
authors.initials: K
authors.lastname: Kuramochi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tsubaki
authors.forename: Kengo
authors.initials: K
authors.lastname: Sakaguchi
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
mesh_terms: D000164:Acremonium / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005399:Fishes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D010944:Plants / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D001578:Benzopyrans; D019384:Nucleic Acid Synthesis Inhibitors; D004256:DNA Polymerase I; D004259:DNA-Directed DNA Polymerase; C095645:dehydroaltenusin