Iron Chelators of the Dipyridylketone Thiosemicarbazone Class: Precomplexation and Transmetalation Effects on Anticancer Activity
journal contributionposted on 2009-01-22, 00:00 authored by Paul V. Bernhardt, Philip C. Sharpe, Mohammad Islam, David B. Lovejoy, Danuta S. Kalinowski, Des R. Richardson
We previously reported a series of di-2-pyridylketone thiosemicarbazone (HDpT) chelators that showed marked and selective antitumor activity (Whitnall, M.; et al. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 14901−14906). To further understand their biological efficacy, we report the characterization and activity of their MnII, CoIII, NiII, CuII, and ZnII complexes. The X-ray crystal structures of four divalent (Mn, Ni, Cu, and Zn) and one trivalent (Fe) complexes are reported. Electrochemistry shows the FeIII/II and CuII/I potentials of the complexes may be redox-active within cells. Stability constants were also determined for the MnII, NiII, CuII, and ZnII complexes. All divalent complexes underwent transmetalation upon encountering FeII, to form low spin ferrous complexes. Importantly, the divalent MnII, NiII, CuII, and ZnII complexes of the HDpT analogues are equally active in preventing proliferation as their ligands, suggesting the complexes act as lipophilic vehicles facilitating intracellular delivery of the free ligand upon metal dissociation.