Organometallic Anticancer Agents: Cellular Uptake and Cytotoxicity Studies on Thiol Derivatives of the Antitumor Agent Molybdocene Dichloride

Abstract

The effect of aqueous solubility, charge, and lability of four thiol derivatives of the antitumor metallocene molybdocene dichloride (Cp 2MoCl2) on the cell uptake and cytotoxicity against V79 Chinese hamster lung cells has been determined. Addition of 4-thiol-2,3,5,6- tetrafluorobenzoic acid, 1-thio-β-D-glucose, and 1-thio-2,3,4,5- tetraacetyl-β-D-glucose to aqueous solutions of molybdocene dichloride afforded the corresponding metallocenes in which the deprotonated thiols are coordinated to the metal center. These metallocenes were studied, along with the previously reported glutathione derivative Cp2Mo(GS)2, which has been proposed to be formed from molybdocene dichloride in blood plasma. In contrast to Cp2MoCl2 which rapidly loses the chloride ligands to form a positively charged aquated complex at pH 7, the thiol derivatives are stable to ligand hydrolysis in 50 mM salt at 37°C for 24 h. Cytotoxicity values determined by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay gave an IC50 value of 350 μM for molybdocene dichloride with V79 cells, with similar values obtained with human breast MCF-7 (620 μM) and ovarian 2008 (700 μM) cell lines. The water-soluble thiol derivatives were not cytotoxic, while the acetylated sugar derivative was insoluble in water or aqueous dimethyl sulfoxide. Cell uptake experiments in which the molybdenum content in cells treated with each metallocene for 24 h was measured by graphite furnace atomic absorption spectroscopy showed that the fluorinated aromatic derivative was most efficiently transported into cells, followed by molybdocene dichloride, with the lowest uptake observed for Cp2Mo(GS)2 and the glucose derivative. The cell uptake results do not correlate with overall charge of the complexes or the measured IC50 values. The distinct cytotoxicity and cell uptake profiles of Cp2MoCl2 compared with Cp 2Mo(GS)2 show that while rapid coordination of Cp 2-MoCl2 to glutathione occurs in water at pH 7, significant deactivation of molybdocene dichloride by conversion to Cp 2Mo(GS)2 does not occur in cells. Show more