Structure-activity relationship for DNA topoisomerase II-induced DNA cleavage by azatoxin analogues

Eighteen analogues of the nonintercalative DNA topoisomerase II (topo II)-active epipodophyllotoxin-ellipticine hybrid, azatoxin, were synthesized and evaluated for their ability to induce topo II-mediated DNA strand breaks in vitro. In general, the SAR profile of the azatoxins showed more homology with that of the epipodophyllotoxins than with the ellipticines. Of the compounds studied, only fluoro substitution at the 8-, 9, and 10-positions of azatoxins enhanced activity, with 9-fluoroazatoxin being the most active compound in this series. Eighteen analogues were synthesized and evaluated for their ability to induce topoisomerase II-mediated DNA strand breaks in vitro. Substitution at the 8-, 9-, and 10-positions of the DNA intercalation/association domain enhanced activity, whereas, any variation in the pendant group domain of our model resulted in decreased topoisomerse II activity.