Investigation of cobalt(iii)–phenylalanine complexes for hypoxia-activated drug delivery

Abstract

Four cobalt(III)–phenylalanine complexes, [Co(Phe)(py₂en)](ClO₄)₂·H₂O (1), [Co(Phe)(TPA)](ClO₄)₂·H₂O (2), [Co(Phe)(py₂enMe₂)](ClO₄)₂·H₂O (3) and [Co(bipy)₂(Phe)](ClO₄)₂·H₂O (4), were investigated as prototype models for hypoxia-activated delivery of melphalan – a phenylalanine derivative anticancer drug of the class of nitrogen mustards. Single crystal X-ray diffraction analysis provided the molecular structures of 1–4, as a single isomer/conformer. According with NMR and theoretical calculations, the solid-state structures of 2 and 4 are maintained in solutions. For complexes 1 and 3, though, a mixture of isomers was found in DMSO solutions: Λ-cisα(exo,exo) and Δ-cisβ₁(exo,exo) for 1 (3 : 2 ratio), and Λ-cisα(exo,exo) and Δ-cisα(exo,exo) for 3 (5 : 1 ratio). Theoretical calculations point to a re-equilibration reaction of the solid-state Λ-cisβ₁ isomer of 1 in solution. Electrochemical analysis revealed a correlation between the electron-donor capacity of the ancillary ligands and the redox potentials of the complexes. The potentials varied from +0.01 for 1 to +0.31 V vs. SHE for 4 in aqueous media and indicate that reduction should be achieved in biological media. The integrity of the complexes in pH 5.5 and 7.4 buffered solutions was confirmed by UV-Vis monitoring up to 24 h at 25 °C. Reduction by ascorbic acid (AA) shows an O₂-dependent dissociation of the L-Phe for complexes 1–3, with higher conversion rates at pH 7.4. For complex 4, a fast dissociation of L-Phe was observed, with conversion rates unaffected by the pH and presence of O₂.