Cobalt(III) complexes are well-suited systems for cytotoxic drug release under hypoxic conditions. Here, we investigate the effect of cytotoxic azide release by cobalt-containing carrier-prototypes for antitumoral prodrugs.
In addition, we study the species formed after reduction of Co(3+)→Co(2+) in the proposed models for these prodrugs. Three new complexes, [Co(III)(L)(N3)2]BF4(1), [{Co(II)(L)(N3)}2](ClO4)2(2), and [Co(II)(L)Cl]PF6(3), L=[(bis(1-methylimidazol-2-yl)methyl)(2-(pyridyl-2-yl)ethyl)amine], were synthesized and studied by several spectroscopic, spectrometric, electrochemical, and crystallographic methods. Reactivity and spectroscopic data reveal that complex 1 is able to release N3(-) either after reduction with ascorbic acid, or by ambient light irradiation, in aqueous phosphate buffer (pH6. 2, 7. 0 and 7. 4) and acetonitrile solutions. The antitumoral activities of compounds 1-3 were tested in normoxia on MCF-7 (human breast adenocarcinoma), PC-3 (human prostate) and A-549 (human lung adenocarcinoma epithelial) cell lines, after 24h of exposure. Either complexes or NaN3 presented IC50 values higher than 200μM, showing lower cytotoxicity than the clinical standard antitumoral complex cisplatin, under the same conditions. Complexes 1-3 were also evaluated in hypoxia on A-549 and results indicate high IC50 data (>200μM) after 24h of exposure. However, an increase of cancer cell susceptibility to 1 and 2 was observed at 300μM. Regarding complex 3, no cytotoxic activity was observed in the same conditions. The data presented here indicate that the tridentate ligand L is able to stabilize both oxidation states of cobalt (+3 and +2). In addition, the cobalt(III) complex generates the low cytotoxic cobalt(II) species after reduction, which supports their use as as carrier prototypes for antitumoral prodrugs.
Journal of inorganic biochemistry. 2016 Jan 27 [Epub ahead of print]
Bianca M Pires, Letícia C Giacomin, Frederico A V Castro, Amanda Dos S Cavalcanti, Marcos D Pereira, Adailton J Bortoluzzi, Roberto B Faria, Marciela Scarpellini
Instituto de Química, Universidade Federal do Rio de Janeiro, 21941-611 Rio de Janeiro, RJ, Brazil. , Instituto de Química, Universidade Federal do Rio de Janeiro, 21941-611 Rio de Janeiro, RJ, Brazil. , Instituto de Química, Universidade Federal do Rio de Janeiro, 21941-611 Rio de Janeiro, RJ, Brazil. , Instituto Nacional de Traumatologia e Ortopedia, Av Brasil 500, Divisão de Pesquisa, São Cristóvão, 20940-070 Rio de Janeiro, RJ, Brazil. , Instituto de Química, Universidade Federal do Rio de Janeiro, 21941-611 Rio de Janeiro, RJ, Brazil. , Departamento de Química, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, SC, Brazil. , Instituto de Química, Universidade Federal do Rio de Janeiro, 21941-611 Rio de Janeiro, RJ, Brazil. , Instituto de Química, Universidade Federal do Rio de Janeiro, 21941-611 Rio de Janeiro, RJ, Brazil.