Design, synthesis, and biological evaluation of a series of fluoroquinoanthroxazines with contrasting dual mechanisms of action against topoisomerase II and G-quadruplexes.

Abstract

Topoisomerase inhibitors are important and clinically effective drugs, while G-quadruplex-interactive compounds that disrupt telomere maintenance mechanisms have yet to be proven useful in the clinic. If G-quadruplex-interactive compounds are to be clinically useful, it will most likely be in combination with more established cytotoxic agents. We have previously reported on a family of topoisomerase II inhibitors that also interact with G-quadruplexes. On the basis of previously established structure-activity relationships (SARs) for compounds that are able to inhibit topoisomerase II or interact with G-quadruplex to varying degrees, we have now designed and synthesized four new fluoroquinoanthroxazines (FQAs) that have different profiles of mixed topoisomerase II poisoning effects and G-quadruplex interactions. The biological profiles of the four new compounds were determined with respect to G-quadruplex interaction (polymerase stop and photocleavage assays) and topoisomerase II interaction (DNA cleavage and kDNA decatenation assays), alongside cytotoxicity tests with matched pairs of topoisomerase II-resistant and topoisomerase II-sensitive cells and with telomerase (+) and ALT (+) cell lines (ALT = alternative lengthening of telomeres). From this study, we have identified two FQAs with sharply contrasting profiles of potent G-quadruplex interaction with a weak topoisomerase II poisoning effect, and vice versa, for further evaluation to determine the optimum combination of these activities in subsequent in vivo studies.

• Authors: Mu-Yong Kim, Wenhu Duan, Mary Gleason-Guzman, Laurence H Hurley
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 46 Issue 4 Pg. 571-83 (Feb 13 2003) ISSN: 0022-2623 [Print] United States
• PMID: 12570378 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Fluoroquinolones
• Oxazines
• Pyrrolidines
• Topoisomerase II Inhibitors
• DNA
• DNA Topoisomerases, Type II

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Division (drug effects)
• DNA (chemistry, drug effects)
• DNA Topoisomerases, Type II (deficiency, metabolism)
• Drug Design
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Fluoroquinolones (chemical synthesis, chemistry, pharmacology)
• Humans
• Oxazines (chemical synthesis, chemistry, pharmacology)
• Pyrrolidines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Telomere
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured