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

• A cobalt(III) complex is proposed as carrier prototype for antitumoral prodrugs.
• 1HNMR and 13CNMR corroborate the proposition of a d6 low-spin cobalt(III) complex.
• Normoxia and hypoxia activities of complex 1 are similar until 200 μM, after 24 h of exposure.
• X-ray crystal data of complexes 1–3 confirm the proposed structures.

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, [CoIII(L)(N3)2]BF4(1), [{CoII(L)(N3)}2](ClO4)2(2), and [CoII(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 (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 μM, 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 μM) after 24 h of exposure. However, an increase of cancer cell susceptibility to 1 and 2 was observed at 300 μM. 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.

Cobalt(III) complexes are well-suited systems for carrier-prototypes of antitumoral prodrugs under hypoxic conditions. Here, the ability of an azido-cobalt(III) complex of releasing azide ions after being reduced with ascorbic acid is confirmed. Two models for the intermediate species formed after the reduction and dissociation of the carrier are provided.Figure optionsDownload as PowerPoint slide