Metal ion Binding Capability of Novel Ambidentate Chelators to Construct Hypoxia Activated Anticancer Drug Candidates

The severe side effects of Pt(II)-based anticancer drugs motivate the development of more selective metallodrugs. One promising approach involves hypoxia-activated Co(III) complexes, which can undergo reduction in the reductive tumor microenvironment and release biologically active ligands. In this study, we designed, synthesized, and characterized a series of ambidentate ligands containing spatially separated O- and N-donor sites, including derivatives of biologically relevant molecules and pharmaceuticals. These ligands were developed as building blocks for heterobimetallic cobalt(III)–platinum-group metal (Co/PGM) complexes with potential selective anticancer activity. Their interactions with [Co(4N)]³⁺ units, Pd(II), and organometallic Ru(II) and Rh(III) ions were investigated using pH-potentiometry, NMR spectroscopy, and ESI-TOF-MS in solution and the solid state. The results provide insight into donor-atom selectivity, structural and redox properties, and the preliminary in vitro anticancer activity of the resulting complexes, supporting their potential as hypoxia-activated anticancer agents.