Inhibition of DNA topoisomerase II catalytic activity by the antiviral agents 7-chloro-1,3-dihydroxyacridone and 1,3,7-trihydroxyacridone.
Previously we reported that the antiproliferative and antiviral actions of 7-chloro-1,3 dihydroxyacridone (compound 1) and its derivatives may be mediated through the inhibition of mammalian DNA topoisomerase II. In the present work, we have extended our investigation into the mechanism of topoisomerase II inhibition by these agents. Both compound 1 and its 7-OH derivative, compound 2, inhibited topoisomerase II catalytic activity in vitro, yet neither agent affected the activity of topoisomerase I. DNA unwinding assays indicated that compound 1 and compound 2 bound to DNA, although no correlation was found between DNA unwinding and topoisomerase II catalytic inhibition. Neither agent enhanced topoisomerase II-mediated DNA cleavage in vitro; however, both compound 1 and compound 2 antagonized breaks induced by etoposide and amsacrine. Experiments indicate that interference with etoposide-stimulated breaks results from inhibition of topoisomerase II * DNA binding by compound 1. These findings suggest that compound 1 and its derivatives may represent a novel structural class of topoisomerase II catalytic inhibitors.
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, 27599, USA.
J R
JR
Vance
K F
KF
Bastow
D000166:Acridines / Q000494:pharmacology*; D000677:Amsacrine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002384:Catalysis; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D010957:Plasmids / Q000235:genetics; D059005:Topoisomerase II Inhibitors
C120264:1,3,7-trihydroxyacridone; C094233:7-chloro-1,3-dihydroxyacridone; D000166:Acridines; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D005047:Etoposide; D004247:DNA