Synthesis and Characterization of Novel Co(III)/Ru(II) Heterobimetallic Complexes as Hypoxia-Activated Iron-Sequestering Anticancer Prodrugs.

Heterobimetallic complexes of an ambidentate deferiprone derivative, 3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one (PyPropHpH), incorporating an octahedral [Co(4N)] (4N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa)) and a half-sandwich type [(η--cym)Ru] (-cym = -cymene) entity have been synthesized and characterized by various analytical techniques. The reaction between PyPropHpH and [Co(4N)Cl]Cl resulted in the exclusive (O,O) coordination of the ligand to Co(III) yielding Co(tren)PyPropHp () and Co(tpa)PyPropHp (). This binding mode was further supported by the molecular structure of Co(tpa)PyPropHp(OH)·6HO () and [Co(tren)PyPropHpH]Cl(PF)·2HO·CHOH (), respectively, obtained via the slow evaporation of the appropriate reaction mixtures and analyzed using X-ray crystallography. Subsequent treatment of or with [Ru(η--cym)Cl] in a one-pot reaction afforded the corresponding heterobimetallic complexes, Co(tren)PyPropHp(η--cym)RuCl () and Co(tpa)PyPropHp(η--cym)RuCl (), in which the piano-stool Ru core is coordinated by the (N,N) chelating set of the ligand. Cyclic voltammetric measurements revealed that the tpa complexes can be reduced at less negative potentials, suggesting their capability to be bioreductively activated under hypoxia (1% O). Hypoxia activation of and was demonstrated by cytotoxicity studies on the MCF-7 human breast cancer cell line. PyPropHpH was shown to be a typical iron-chelating anticancer agent, raising the mRNA levels of TfR1, Ndrg1 and p21. Further qRT-PCR studies provided unambiguous evidence for the bioreduction of after 72 h incubation under hypoxia, in which the characteristic gene induction profile caused by the liberated iron-sequestering PyPropHpH was observed.