Review: DNA molecular electrostatic potential: novel perspectives for the mechanism of action of anticancer drugs involving electron transfer and oxidative stress.

This report examines the mechanism of action of DNA-binding anticancer drugs that involve electron transfer and oxidative stress, and primarily focuses on neglected issues surrounding molecular electrostatic potentials (MEP), the energetics of initial guanine oxidation and the consequences of the sequence dependence of DNA structure on electron transport within a DNA duplex. We argue that an appreciation of electrostatic effects aids in shaping a more complete view of the electron transfer and DNA oxidation process. Some aspects concerning the MEP of DNA relevant to these events have lain dormant, whereas others represent novel insights. We discuss the impact of electrostatics on ligand binding to DNA, guanine oxidation, axial charge transport and hopping termination reactions. Another ignored feature for intercalating redox-active agents is the reversible nature of their interaction with DNA, which in principle permits catalytic regeneration of the unmodified ligand via redox cycling with generation of reactive oxygen species. Therefore, oxidative stress may be exerted on DNA at both ends of the charge transport chain. Hence, mechanistic treatments that neglect to take into account the importance of the MEP of DNA may be flawed or deficient in many cases. An increased understanding of the basic mechanisms of redox chemistry within DNA may aid in improved anticancer drug design.