Organometallic anticancer agents: cellular uptake and cytotoxicity studies on thiol derivatives of the antitumor agent molybdocene dichloride.
The effect of aqueous solubility, charge, and lability of four thiol derivatives of the antitumor metallocene molybdocene dichloride (Cp(2)MoCl(2)) 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-beta-d-glucose, and 1-thio-2,3,4,5-tetraacetyl-beta-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 Cp(2)Mo(GS)(2), which has been proposed to be formed from molybdocene dichloride in blood plasma. In contrast to Cp(2)MoCl(2) 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 degrees C for 24 h. Cytotoxicity values determined by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay gave an IC(50) value of 350 microM for molybdocene dichloride with V79 cells, with similar values obtained with human breast MCF-7 (620 microM) and ovarian 2008 (700 microM) 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 Cp(2)Mo(GS)(2) and the glucose derivative. The cell uptake results do not correlate with overall charge of the complexes or the measured IC(50) values. The distinct cytotoxicity and cell uptake profiles of Cp(2)MoCl(2) compared with Cp(2)Mo(GS)(2) show that while rapid coordination of Cp(2)MoCl(2) to glutathione occurs in water at pH 7, significant deactivation of molybdocene dichloride by conversion to Cp(2)Mo(GS)(2) does not occur in cells.
Waern
Jenny B
JB
School of Chemistry and Electron Microscope Unit, Australian Key Centre for Microscopy and Microanalysis, The University of Sydney, New South Wales 2006, Australia.
Dillon
Carolyn T
CT
Harding
Margaret M
MM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008982:Molybdenum; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D013438:Sulfhydryl Compounds; C024389:molybdocene dichloride; D008982:Molybdenum