Azido- and chlorido-cobalt complex as carrier-prototypes for antitumoral prodrugs

作者：Pires Bianca M; Giacomin Leticia C; Castro Frederico A V; Cavalcanti Amanda dos S; Pereira Marcos D; Bortoluzzi Adailton J; Faria Roberto B; Scarpellini Marciela

来源：Journal of Inorganic Biochemistry, 2016, 157: 104-113.

DOI：10.1016/j.jinorgbio.2016.01.024

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 Co3+ -> Co2+ in the proposed models for these prodrugs. Three new complexes, [Co-III(L)(N-3)(2)]BF4 (1), [{Co-II(L)(N-3)}(2)](ClO4)(2) (2), and [Co-II(L)Cl]PF6 (3), L = [(bis(1-methylimidazol-2-yl)methyl)(2-(pyridy1-2-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 N-3(-) either after reduction with ascorbic acid, or by ambient light irradiation, in aqueous phosphate buffer (pH 6.2, 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 24 h of exposure. Either complexes or NaN3 presented IC50 values higher than 200 NI, 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 (>200 mu M) after 24 h of exposure. However, an increase of cancer cell susceptibility to 1 and 2 was observed at 300 mu M. 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.

• 出版日期2016-4