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

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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.

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

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15 Apr 2020
14 Jul 2020
First published
14 Jul 2020

Dalton Trans., 2020, Advance Article
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Investigation of cobalt(III)–phenylalanine complexes for hypoxia-activated drug delivery

I. C. A. de Souza, S. D. S. Santana, J. G. Gómez, G. P. Guedes, J. Madureira, S. M. D. O. Quintal and M. Lanznaster, Dalton Trans., 2020, Advance Article , DOI: 10.1039/D0DT01389G

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