title: Discovery of a statistically significant and interpretable relationship between redox reactivity and lethality of drugs.
abstract: 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.
authors.affiliation: Department of Industrial and Systems Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong. pangsiukwong@gmail.com
authors.forename: Siu-Kwong
authors.initials: SK
authors.lastname: Pang
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D007928:Lethal Dose 50; D051379:Mice; D010084:Oxidation-Reduction; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000633:toxicity*
chemical_list: D059005:Topoisomerase II Inhibitors; D003577:Cytochrome P-450 Enzyme System