A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane).
A series of twelve structurally related bisdioxopiperazines that included ICRF-187 (dexrazoxane), ICRF-159 (razoxane), ICRF-193, and ICRF-154 were examined both for their ability to inhibit the growth of Chinese hamster ovary (CHO) cells and their ability to inhibit the catalytic activity of mammalian DNA topoisomerase II. The bisdioxopiperazines exhibited a wide range in both growth inhibitory effects (30,000-fold), and in their ability to inhibit the catalytic activity of topoisomerase II (150-fold). The cytotoxicity of the bisdioxopiperazines toward CHO cells was highly correlated (correlation coefficient r = 0.86, P = 0.0003) with their inhibition of the catalytic activity of DNA topoisomerase II. This result strongly suggests that DNA topoisomerase II is the functional target of the bisdioxopiperazines. The stereoisomers (+)-ICRF-187 and (-)-ICRF-186 were observed to be equally cytotoxic and equally inhibitory toward DNA topoisomerase II. This result indicates that the bisdioxopiperazine binding site on DNA topoisomerase II is large enough or flexible enough to accommodate either form of the drug. The strongly metal-ion binding fully rings-opened hydrolysis product of ICRF-187, ADR-925, demonstrated no measurable inhibitory activity toward DNA topoisomerase II or cytotoxicity toward CHO cells.
Hasinoff
B B
BB
Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
Kuschak
T I
TI
Yalowich
J C
JC
Creighton
A M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003603:Cytotoxins / Q000494:pharmacology*; D007739:L Cells; D051379:Mice; D011929:Razoxane / Q000031:analogs & derivatives*; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D003603:Cytotoxins; D059005:Topoisomerase II Inhibitors; D011929:Razoxane