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Rational Design and Molecular Effects of a New Topoisomerase II Inhibitor, Azatoxin¹

Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 [F. L., A. O., Y. P.], and Department of Chemistry, University of Virginia, Charlottesville, VA 22901 [J. M., T. J. C., E. L., T. M.]

Azatoxin [NSC 640737-M; 5.R,11aS-1H,6H,3-one-5,4,11,11a-tetrahydro-5-(3,5-dimethoxy-4-hydroxyphenyl) oxazolo (3',4':1,6)pyrido-(3,4-b)indole] was rationally designed from a model for the pharmacophore of drugs with topoisomerase II inhibition activity. This pharmacophore has at least 2 domains: a quasiplanar polycyclic ring system proposed to bind between the DNA base pairs and a pendant substituent proposed to interact with the enzyme and/or to the DNA grooves. The present study shows that, in cell free systems, azatoxin induces a large number of double strand-breaks in linear Simian virus 40 and human c-myc DNA. These breaks yield cleavage patterns that are different from those of well established topoisomerase II inhibitors (epipodophyllotoxins, amsacrine, mitoxantrone). Azatoxin also inhibits the catalytic activity of purified topoisomerase II, and is a nonintercalator. The structure-activity relationship of 3 isomers and 6 derivatives of azatoxin shows a stringent stereochemical requirement for activity. The effects of azatoxin pendant ring substitution on topoisomerase II mediated DNA cleavage activity were similar to the relationship observed for etoposide.

¹ This work was funded in part through NIH Grant CA54347 (T. M.). F. L. received fellowship support from the French Government through the Foreign Ministry (Lavoisier Fellowship).

² To whom requests for reprints should be addressed, at Building 37, Room 5C27, National Institutes of Health, Bethesda, MD 20892.

Received 2/24/92. Accepted 6/ 8/92.

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