Evaluation of 5-hydroxy-1,4-naphthoquinone-cobalt(III) complexes for hypoxia-activated drug delivery

• Published in: Journal of inorganic biochemistry 2019-10, Vol.199, p.110756-110756, Article 110756
• Main Authors: de Mello, Marcos Vinícius Palmeira, Cebrián-Torrejón, Gerardo, Pereira, Jonas Ramos, dos Santos Moreira, Caroline, Gomes, Carinne Borges de Souza Moraes Rego, da Rocha, David Rodrigues, de Souza Fagundes, Elaine Maria, Ferreira, Glaucio Braga, Lanznaster, Mauricio
• Format: Article
• Language: English
• Subjects: Chemical Sciences
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2019.110756

Three novel Py2N2-cobalt(III) complexes with the 5-hydroxy-1,4-naphthoquinone nuclei (NQ) were evaluated as potential hypoxia-activated anticancer prodrugs. The complexes were synthesized and fully characterized by IR and UV–Visible spectroscopies, ESI mass spectrometry and CHN elemental analysis. Structural information was obtained from density functional theory (DFT) calculations. Cyclic voltammetry analysis in acetonitrile indicates that the ligand substituents (H, CH3 and p-tolylthio) do not have a relevant effect on the Co3+/Co2+ redox potential. Reactions with ascorbic acid in phosphate buffers were performed to simulate redox activation of the complexes in biological media. Fast and irreversible dissociation of the NQ ligands was observed for all complexes upon Co3+/Co2+ reduction. Cytotoxic activity of complexes 1 and 3 was evaluated in tumor cells (HT-29 and HCT-116) under hypoxic and normoxic conditions. Fast and irreversible dissociation of the naphthoquinone ligands was observed for all complexes upon Co3+/Co2+ redox activation by ascorbic acid in phosphate buffer. Despite the lack of selectivity for hypoxia, the complexes were more cytotoxic to tumor cells when compared to the free naphthoquinones, under hypoxic and normoxic conditions. [Display omitted] •CoIII complexes were designed to coordinate cytotoxic 5-hydroxy-1,4-naphthoquinones.•The complexes were evaluated as potential hypoxia-activated anticancer prodrugs.•Biological redox activation was simulated using ascorbic acid as reducing agent.•Fast dissociation of the naphthoquinones occurred upon Co3+/Co2+ reduction.•Complexes are highly cytotoxic against colon cancer cells under hypoxia and normoxia.