Theoretical studies of the reactivity of model systems for the pharmacophores of the anthracycline family of drugs will be undertaken using semiempirical formalisms. (AM1, AM1-SM1/SM2, ETC). The thrust of these studies is to gain insight from quantum chemistry/pharmacology, molecular modeling and statistical inference to understand molecular- level features that govern chemical reactivity but are concealed by the molecular structure and raw experimental data. Electronic properties (absolute electronegativity and hardness; HOMO, LUMO and SOMO orbital energies; enthalpy of reaction for electron attachment; free energies of solvation, etc.) of some 16 and 42 derivatives of naphthaquinone and anthraquinone, respectively, will be calculated and used as variables for the purpose of correlating the variables with experimental one- and two- electron reduction potentials. The electronic properties will also be correlated with antitumor activity (ED25) and acute toxicity (LD50) for those cases where such data are available. Simulated annealing techniques will be used to study the relative stabilities of conformers/rotamers, keto-enol forms and radicals. Solvation free energies will be calculated to determine their (or, in combination with other electronic properties) possible correlations with reduction potentials, antitumor activity (ED25) and acute toxicity (LD50). The studies will be used to develop structure/activity relationships which will, in turn, be used to predict the biological activities of theoretical models - not yet-synthesized-drugs.
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