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.
Madalengoitia
J S
JS
Department of Chemistry, University of Virginia, Charlottesville 22901, USA.
Tepe
J J
JJ
Werbovetz
K A
KA
Lehnert
E K
EK
Macdonald
T L
TL
D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D006868:Hydrolysis; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
D007211:Indoles; C075996:azatoxin; D004247:DNA; D004250:DNA Topoisomerases, Type II