title: Dehydroaltenusin is a specific inhibitor of mammalian DNA polymerase α.
abstract: BACKGROUND
  We carried out a screen for small molecule selective inhibitors of eukaryotic DNA polymerases (pols). Dehydroaltenusin, isolated from a fungus (Alternaria tenuis), was found to be a specific inhibitor of pol α.
  
  
  METHODS
  We succeeded in chemically synthesizing dehydroaltenusin along with five analogs. Of these compounds, dehydroaltenusin was the strongest and most specific inhibitor of mammalian pol α, with an IC(50) value of 0.68 μM. The inhibitory mode of action of dehydroaltenusin against mammalian pol α activity was competitive with respect to the DNA template primer and non-competitive with respect to the 2'-deoxyribonucleoside 5'-triphosphate substrate. Dehydroaltenusin inhibited the cell proliferation of a human cervical cancer cell line, HeLa, by arresting the cells at the S-phase, and preventing the incorporation of thymidine into the cells. These observations indicate that dehydroaltenusin blocks in vivo DNA replication by inhibiting pol α.
  
  
  CONCLUSIONS
  Dehydroaltenusin was effective in suppressing the growth of solid tumors and, therefore, is of interest as a candidate drug for anti-cancer treatment.
authors.affiliation: Kobe-Gakuin University, Department of Nutritional Science, Laboratory of Food and Nutritional Sciences, Kobe, Hyogo, Japan. mizushin@nutr.kobegakuin.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
authors.forename: Naoki
authors.initials: N
authors.lastname: Maeda
authors.forename: Isoko
authors.initials: I
authors.lastname: Kuriyama
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008322:Mammals / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology
chemical_list: D001578:Benzopyrans; D004791:Enzyme Inhibitors; D004256:DNA Polymerase I; C095645:dehydroaltenusin