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 inclu ded ICRF-187 (dexrazoxane), ICRF-159 (razoxane), ICRF-193, and ICRF-15 4 were examined both for their ability to inhibit the growth of Chines e hamster ovary (CHO) cells and their ability to inhibit the catalytic activity of mammalian DNA topoisomerase II. The bisdioxopiperazines e xhibited a wide range in both growth inhibitory effects (30,000-fold), and in their ability to inhibit the catalytic activity of topoisomera se II (150-fold). The cytotoxicity of the bisdioxopiperazines toward C HO cells was highly correlated (correlation coefficient r = 0.86, P = 0.0003) with their inhibition of the catalytic activity of DNA topoiso merase II. This result strongly suggests that DNA topoisomerase Ii is the functional target of the bisdioxopiperazines. The stereoisomers ()-ICRF-I87 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 la rge enough or flexible enough to accommodate either form of the drug. The strongly metal-ion binding fully rings-opened hydrolysis product o f ICRF-187, ADR-925, demonstrated no measurable inhibitory activity to ward DNA topoisomerase II or cytotoxicity toward CHO cells.