An Esculetin–Cobalt(III) Archetype for Redox‐Activated Drug Delivery Platforms with Hypoxic Selectivity

The motivation of this work was to probe whether coordination of esculetin to cobalt(III) could lead to a complex with the required properties to function as a redox‐activated drug delivery platform, selective for hypoxic environments. The complex [Co(esc)(py2en)]ClO4·(CH3OH)2 (1) was obtained and fully characterized by CHN elemental analysis, single‐crystal X‐ray diffractometry, UV/Vis and fluorescence spectroscopy, and ESI mass spectrometry. The redox behavior of 1 was evaluated by cyclic and square wave voltammetry analyses in MeCN and PBS buffer, which revealed distinct potentials for the Co3+/Co2+ processes in aqueous and organic solutions. In PBS, the potential is within the accepted ideal range (–0.2 to –0.4 V vs. SHE) for reduction in biological systems. Thus, a selective release of the coumarin ligand in a hypoxic environment upon reduction was simulated by investigating reactions of 1 with sodium dithionite in argon‐, air‐, and O2‐saturated atmospheres. An [O2]‐dependent dissociation of esculetin was monitored over a 72 h period at 25 °C by UV/Vis spectroscopy and confirmed by fluorescence spectroscopy and ESI‐MS data. These results provide strong evidence of a hypoxia‐selective, redox‐activated mechanism for the release of esculetin from this cobalt(III) complex. A cobalt(III)–esculetin complex was evaluated as a hypoxia‐selective, redox‐activated drug delivery platform. The Co3+/Co2+ potential in PBS buffer was found within the ideal range (–0.2 to –0.4 V) for reduction in vivo. Reactions with Na2S2O4, monitored by UV/Vis spectroscopy in PBS buffer, showed an [O2]‐dependent dissociation of esculetin.