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

Abstract

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.

Investigation of Cobalt(III)‐Tetrachlorocatechol Complexes as Models for Catechol‐Based Anticancer Prodrugs

“…Thus, the redox potential for Co 3+ /Co 2+ was found to be –0.91 ± 0.02 V and –1.15 ± 0.02 V vs. Fc/Fc + for 1 and 2 , respectively. These redox potentials are in the range of those reported for the complexes [Co(CAT)(TPA)]ClO 4 (CAT = 2,3‐naphthyldiol) ( E pc = –1.02 V vs. Fc/Fc + in DMF), [Co(Br 4 Cat)(L)] + (–1.07 to –1.64 V vs. Fc/Fc + in MeCN), [Co(Me 3 TPA)(TCC)] + (–0.4 V vs. Fc/Fc + in MeCN), and [Co(esc)(py 2 en)] + (esc = esculetin) ( E 1/2 = –1.00 V vs. Fc/Fc + in MeCN) …”

“…This result was associated to the redox potential for the Co 3+ /Co 2+ , which is too negative to allow reduction by ascorbic acid. Nonetheless, in a recent paper published by our group, successful release of esculetin (or 6,7‐dihydroxycoumarin) from the complex [Co(esc)(py 2 en)]ClO 4 upon Co 3+ /Co 2+ reduction by dithionite was observed, with an oxygen‐dependent dissociation rate . Interestingly, the redox potential of this complex in MeCN (–1.00 V vs. Fc/Fc + ) is similar to that measured in DMF for [Co(CAT)(TPA)]ClO 4 (–1.02 V vs. Fc/Fc + ) .…”

“…Nonetheless, in a recent paper published by our group, successful release of esculetin (or 6,7-dihydroxycoumarin) from the complex [Co(esc)(py 2 en)]ClO 4 upon Co 3+ /Co 2+ reduction by dithionite was observed, with an oxygen-dependent dissociation rate. [26] Interestingly, the redox potential of this complex in MeCN (-1.00 V vs. Fc/Fc + ) is similar to that measured in DMF for [Co(CAT)(TPA)]ClO 4 (-1.02 V vs. Fc/Fc + ). [25] Thus, we have decided to further investigate this class of complexes, using tetrachorocatechol as a drug model for cobalt(III)-catechol prodrugs.…”

“…Nonetheless, the complex [Co(esc)(py 2 en)]ClO 4 did also present a potential in MeCN in the same range (–1.0 V vs. Fc/Fc + ), and was reduced by dithionite with an [O 2 ]‐dependent dissociation of esculetin. Still, the Co 3+ /Co 2+ potential measured in aqueous solution for [Co(esc)(py 2 en)]ClO 4 was –0.24 V vs. SHE, within the ideal range for reduction in biological conditions . Unfortunately, we were unable to obtain useful electrochemical data in aqueous solutions due to the very low solubility of 1 and 2 , even by addition of DMSO.…”

“…These redox potentials are in the range of those reported for the complexes [Co(CAT)(TPA)]ClO 4 (CAT = 2,3-naphthyldiol) (E pc = -1.02 V vs. Fc/Fc + in DMF), [25] [Co(Br 4 Cat)(L)] + (-1.07 to -1.64 V vs. Fc/Fc + in MeCN), [40] [Co(Me 3 TPA)(TCC)] + (-0.4 V vs. Fc/Fc + in MeCN), [27] and [Co(esc)(py 2 en)] + (esc = esculetin) (E 1/2 = -1.00 V vs. Fc/Fc + in MeCN). [26] Hz. A glassy carbon (BASi) was used as working electrode, a platinum wire was used as counter electrode, a Ag/AgCl for organic solvent (BASi) was used as reference electrode and ferrocene [41] was used as internal reference.…”