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HIGHLY POTENT EXTRANUCLEAR-TARGETED LUMINISCENT IRIDIUM(III) ANTITUMOR AGENTS CONTAINING BENZIMIDAZOLE-BASED LIGANDS
Autores:
GLORIA VIGUERAS BAUTISTA
,
SERGIO ALEJO PÉREZ HENAREJOS
, JYOTI YELLOL, GORAKH YELLOL, JURAJ ZAJAC,
ANTONIO DONAIRE GONZÁLEZ
, VOJTECH NOVOHRADSKY, CHRISTOPH JANIAK, VIKTOR BRABEC,
JOSE RUIZ LÓPEZ
,
Grupos de investigación:
[GI/IMIB/E110/2011] Metalofámacos antitumorales no convencionales
Comunicación:
Antecedentes:
Group 9 metal complexes based on iridium and rhodium have recently arisen as fascinating potential alternatives to existing platinum and ruthenium metallodrugs. In this regard, iridium complexes have been studied extensively as new agents for biomedical applications used as chemical and biological probes, and as antitumor agents. On the other hand, benzimidazole has been shown to be a widely used pharmacophore, and some benzimidazole half-sandwich iridium(III) compounds have been recently shown by us to act either as anti-angiogenic agents or inhibitors of amyloid-beta-aggregation.
Métodos:
In this work, we focus our interest on a series of 6 substitutionally inert and luminiscent iridium(III) antitumor agents of the type [Ir(C^N)2(N^N)][PF6] containing a benzimidazole N^N ligand with an ester group as a handle for further functionalization and a butyl group for N-substitution chosen initially aiming to lipophilic properties of final complex, together with various C^N ligands based on 2-phenylbenzimidazole and 1-phenylpyrazole. All synthetic manipulations were carried out under an atmosphere of dry, oxygen-free nitrogen using standard Schlenk techniques. Stock solutions for cellular studies were prepared by dissolving the iridium compounds in DMSO. The final DMSO concentration in culture medium didn’t exceed 0.4 % (v/v). Cisplatin (CDDP) stock solution was prepared by dissolving CDDP in ultrapure water (Milli-Q).
Resultados:
These iridium compounds are highly cytotoxic in A2780 cancer cells (approximately 7x more cytotoxic than CDDP) and also in breast cancer cells (approximately 100x more cytotoxic than CDDP in MDA-MB-231 cells in most cases). All complexes (except one of them) were found to be less toxic than CDDP in a kidney healthy cell line, BGM. Confocal microscopic studies were performed with human ovarian carcinoma cells A2780 treated with one of the phosphorescent iridium compound. Stable and bright luminiscence of this compound allowed us to evaluate cellular localization after the treatment of the cells. The predominant accumulation was observed in the cytoplasm of the cells and it is of interest that the iridium complexes localized mainly in the actin cortex. On the other hand, the production of reactive oxygen species (ROS) and the mitochondria membrane potential were studied by flow cytometry in A2780 cells. After incubation of cells for 24 h, the resulting fluorescence was measured. Compounds decreased the production of ROS in this cell line without modifying the mitochondria membrane potential.
Conclusiones:
These compounds exhibit IC50 values in the high nanomolar range in some ovarian and breast cancer cell lines while most of them showing low cytotoxicity in the nontumorigenic BGM cells. In addition, they are located in the actin cortex predominantly as shown by confocal luminiscence microscopy. Furthermore, they decrease the production of ROS in A2780 without modifying the mitochondria membrane potential. These results have the potential to open up the door to a new large family of drug bioconjugates and theranostic agents.
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