Butylanilinouracil: a selective inhibitor of HeLa cell DNA synthesis and HeLa cell DNA polymerase alpha.
A series of 6-anilinouracils, dGTP analogues which selectively inhibit specific bacterial DNA polymerases, were examined for their capacity to inhibit purified DNA polymerases from HeLa cells. The p-n-butyl derivative (BuAU) was found to inhibit DNA polymerase alpha with a Ki of approximately 60 microM. The inhibitory effect of BuAU was reversed specifically by dGTP and was observed only for DNA polymerase alpha; polymerases beta and lambda were not inhibited by drug at concentrations as high as 1 mM. BuAU also was inhibitory in vivo in HeLa cell culture; at 100 microM it reversibly inhibited cell division and selectively depressed DNA synthesis. The results of these studies indicate that BuAU is an inhibitor with considerable potential as a specific probe with which to dissect the structure of mammalian polymerase alpha and its putative role in cellular DNA replication.
D009189:Avian Myeloblastosis Virus / Q000201:enzymology; D001412:Bacillus subtilis / Q000201:enzymology; D004256:DNA Polymerase I / Q000378:metabolism; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors*; D004258:DNA Polymerase III / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D004926:Escherichia coli / Q000201:enzymology; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
D004273:DNA, Neoplasm; D019384:Nucleic Acid Synthesis Inhibitors; D014498:Uracil; C024095:butylanilinouracil; D012194:RNA-Directed DNA Polymerase; D004256:DNA Polymerase I; D004257:DNA Polymerase II; D004258:DNA Polymerase III