Iron Chelators in Medicinal Applications - Chemical Equilibrium Considerations in Pharmaceutical Activity

Thomas      Manning; Greg      Kean; Jessica      Thomas; Khaleh      Thomas; Michael      Corbitt; Donna      Gosnell; Ronald      Ware; Sonya      Fulp; Joey      Jarrard; Dennis      Phillips

doi:10.2174/092986709788682128

Abstract

Iron chelators are being examined as a potential class of pharmaceutical agents to battle different types of cancer as well as iron overload diseases. In recent studies, iron binding species such as desferrioxamine, triapine, tachpyridine, Dp44Mt, and PIH have been tested in cell line tests and clinical trials. Using published chemical equilibrium values (stability constants, equilibrium constants), it is argued that an iron chelator cannot competitively remove iron from a heme-containing biomolecule (i.e. hemoglobin (Hb), myoglobin) causing a cancerous cell to die. This type of reaction (DFO(aq) + [Fe , -Hb] → [Fe , -DFO] + Hb) has been proposed in a number of published studies using circumstantial evidence. It is argued that iron chelators can potentially interact with iron from ferritin or iron that has precipitated or flocculated as oxyhydroxide under physiological pHs. It is argued that chelators can interfere with various physiological processes by binding cations such as Ca2+, Zn2+ or K+. A number of siderophores and natural products that have the ability to bind Fe /Fe as well as other cations are discussed in terms of their potential pharmaceutical activity as chelators. Chemical equilibria between cations and pharmaceutical agents, which are rarely quantitated in explaining medicinal mechanisms, are used to show that chelators can bind and remove iron and other cations from physiologically important systems required for cell survival and propagation.

Keywords: Chelator, iron, calcium, EDTA, mechanism, DFO, triapine, tachpyridine, PIH, cancer