Prediction of initial reduction potentials of compounds related to anthracyclines and implications for estimating cardiotoxicity.

Eighteen anthracyclines representing several different structural classes were found in the literature to have their respective redox potentials measured under near-identical conditions. The initial reductions were determined in terms of half-wave potentials (HWPs). The electronic structures of these 18 anthracyclines were optimized, and the resulting electronic descriptor measures were regressed against the HWPs. A very significant linear correlation (QSAR) was found between HWP and the lowest unoccupied molecular orbital (LUMO) energy by using both the CNDO/2 and MNDO one-electron molecular orbital methods. These findings suggest that it may be possible to estimate the HWP of an anthracycline in advance of its synthesis. Insofar as the redox potential, as represented by HWP, is an indicator of the relative degree of cardiotoxicity of an anthracycline, it may also be possible to rank relative cardiotoxicity for chemical classes of anthracycline analogues in terms of the identified QSAR.