AK37: the first pyridoacridine described capable of stabilizing the topoisomerase I cleavable complex

Anticancer Drugs. 2004 Oct;15(9):907-13. doi: 10.1097/00001813-200410000-00012.

Abstract

Pyridoacridines are marine natural products that contain planar structures. Almost all are cytotoxic and capable of DNA intercalation. Several pyridoacridines have demonstrated anti-cancer activity, being able to generate reactive oxygen species or to inhibit topoisomerase (Topo) II. Synthetic pyridoacridines were characterized and compared to other pyridoacridines as well as the Topo-inhibiting drugs (etoposide, 9-aminocamptothecin and wakayin) in a series of in vitro enzyme systems. We found AK37 was able to stabilize a DNA-Topo I cleavable complex, but not a DNA-Topo II cleavable complex. To our knowledge, this is the first report of a DNA-Topo I cleavable complex stabilizing pyridoacridine. Structure comparison studies demonstrated that this activity was lost when an extra 'F' ring was added, but activity was not affected when the 'D' ring was removed. AK37 inhibited the catalytic activity of both human Topo I and II.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acridines / chemistry*
  • Acridines / toxicity*
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / toxicity
  • CHO Cells
  • Cell Line, Tumor
  • Cricetinae
  • DNA Damage*
  • DNA Topoisomerases, Type I / genetics
  • DNA Topoisomerases, Type I / metabolism*
  • DNA Topoisomerases, Type II / genetics
  • DNA Topoisomerases, Type II / metabolism
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor / methods
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / toxicity
  • Enzyme Stability / drug effects
  • Enzyme Stability / physiology
  • Humans
  • Intercalating Agents / chemistry*
  • Intercalating Agents / toxicity*
  • Phenanthrolines / chemistry*
  • Phenanthrolines / toxicity*
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors

Substances

  • AK37 compound
  • Acridines
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Intercalating Agents
  • Phenanthrolines
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • pyridoacridine
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II