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

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.
Authors	Kathryn M Marshall, Joseph A Holden, Avi Koller, Yoel Kashman, Brent R Copp, Louis R Barrows
Journal	Anti-cancer drugs (Anticancer Drugs) Vol. 15 Issue 9 Pg. 907-13 (Oct 2004) ISSN: 0959-4973 [Print] England
PMID	15457132 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References	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
Topics	Acridines (chemistry, toxicity) Animals Antineoplastic Agents (chemistry, toxicity) CHO Cells Cell Line, Tumor Cricetinae DNA Damage DNA Topoisomerases, Type I (genetics, metabolism) DNA Topoisomerases, Type II (genetics, metabolism) Dose-Response Relationship, Drug Drug Screening Assays, Antitumor (methods) Enzyme Inhibitors (chemistry, toxicity) Enzyme Stability (drug effects, physiology) Humans Intercalating Agents (chemistry, toxicity) Phenanthrolines (chemistry, toxicity) Topoisomerase I Inhibitors Topoisomerase II Inhibitors

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