Improved cytotoxicity of pyridyl-substituted thiosemicarbazones against MCF-7 when used as metal ionophores
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 Mn(II), Co(III), Ni(II), Cu(II), and Zn(II) complexes. The X-ray crystal structures of four divalent (Mn, Ni, Cu, and Zn) and one trivalent (Fe) complexes are reported. Electrochemistry shows the Fe(III/II) and Cu(II/I) potentials of the complexes may be redox-active within cells. Stability constants were also determined for the Mn(II), Ni(II), Cu(II), and Zn(II) complexes. All divalent complexes underwent transmetalation upon encountering Fe(II), to form low spin ferrous complexes. Importantly, the divalent Mn(II), Ni(II), Cu(II), and Zn(II) 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.