A statistically significant and interpretable relationship between electrophilicity as a redox reactivity indicator and LD50 as a
lethality indicator of drugs was discovered, and this relationship could be interpreted by the action of the cytochrome P450. The drugs
chosen in this study were Topoisomerase II inhibitor anticancer drugs, and the electrophilicity of drugs was obtained by quantum chemical
calculation. Since the P450 detoxification mechanism is the catalytic oxidation of drug molecules, it may infer that the drug molecules
being easily oxidized (low electrophilicity) will be weak in lethality in general. In addition, this relationship revealed two structural
scaffolds for the anthracycline-based topoisomerase II inhibitors, and their lethality mechanisms are not totally the same. Such relationship
can assist in designing new drugs that candidates possessing low electrophilicity are recommended for lowering of lethality, and
moieties providing a large inductive effect can reduce the electrophilicity of the anthracycline-based topoisomerase II inhibitors.
Keywords: Anticancer drugs, cytochrome P450, electrophilicity, lethality, QSAR, topoisomerase II inhibitors.
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