title: Actions of derivatives of dehydroaltenusin, a new mammalian DNA polymerase alpha-specific inhibitor.
abstract: Dehydroaltenusin was found to be an inhibitor of mammalian DNA polymerase alpha (pol. alpha) in vitro, but did not influence the activities of the other replicative DNA polymerases including even other vertebrate pol. alpha. In this study, we purified or synthesized various slightly modified derivatives of dehydroaltenusin, and using them, investigated the relationship between the chemical structure and the inhibitory effects, and the in vitro and in vivo effects of dehydroaltenusin to determine to what extent the pol. alpha activity inhibition influences cell proliferation. Most of the derivatives lost the enzyme species-specific inhibitory effect, suggesting that dehydroaltenusin is three-dimensionally inserted into a pocket present only in mammalian pol. alpha. Dehydroaltenusin inhibited the cell proliferation of the human gastric cancer cell line NUGC-3 by arresting the cells at G1/S-phase, and prevented the incorporation of thymidine into the cells, indicating that it blocks the primary step of in vivo DNA replication by inhibiting pol. alpha. This compound also induced apoptosis of the cells. Dehydroaltenusin is a mammalian pol. alpha-specific inhibitor useful in both of in vivo and in vitro experiments.
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Chikako
authors.initials: C
authors.lastname: Murakami
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ohta
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Kengo
authors.initials: K
authors.lastname: Sakaguchi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
mesh_terms: D000818:Animals; D017209:Apoptosis; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008322:Mammals
chemical_list: D001578:Benzopyrans; D004791:Enzyme Inhibitors; D004256:DNA Polymerase I; D019951:DNA Polymerase beta; C095645:dehydroaltenusin