Molecular-level features that govern chemical reactivity are often concealed by the molecular structure and raw experimental data. To understand these features in the case of the anthracyclines, density functional theory (DFT)-based reactivity descriptors, spin densities and classical quantum chemical properties will be determined from first principles calculations for the purpose of examining the inherent reactivities of the biomedically important anthracyclines: adriamycin (AD) and daunomycin (DN), and their analogues 5-iminodaunomycin (5IDN) and aclacinomycin A (ACM A). For computational efficiency, model systems for the presumed pharmacophores of the drugs will be used: 5,8-dihydroxy-1,4-naphthaquinone (juglone) for ACM A. Other simplified model systems but more closely-related to the quinone and semi quinone methides-or the methides themselves-of the drugs will also be investigated. In particular, parameters/factors governing the redox chemistry of the drugs and some unresolved structure/activity relationships will be probed using, in a unified way, properties intimately related to the redox chemistry of the drugs, the condensed Fukui function, softness reactivity indices (within the frame work of the local version of the HSAB principles) and spin densities to get insight into ways of separating the anti-tumor activity from the cardiotoxic effects, and the mode of actions of the drugs, particularly as they relate to cardiotoxicity and cytotoxicity. These studies can be anticipated to stimulate ideas for systematic and rational drug design for improved medicinal activity whereby the anti-tumor efficacy is retained while the cardiotoxic effects are minimized.
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