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)(py(2)en)]ClO4 center dot(CH3OH)(2) (1) was obtained and fully characterized by CHN elemental analysis, single-crystal Xray 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 O-2-saturated atmospheres. An [O-2]-dependent dissociation of esculetin was monitored over a 72 h period at 25 degrees 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.