Cytotoxicity of a Series of Ferrocene-containing β-Diketones

Background: Oxidised ferrocenium compounds often possess antineoplastic activity. In contrast, reduced ferrocene derivatives firequently only show activity if cell components can oxidise them inside cells to the ferrocenium species. Ferrocene compounds having the lowest formal reduction potential are normally expected to be the most cytotoxic. Here we demonstrate this is not always the case. Some of the structure-related and physical properties that enhance ferrocenyl antineoplastic activity have been investigated. Materials and Methods: Ferrocene-containing beta-diketones of the type FcCOCH(2)COR with Fc=ferrocenyl and R=CF3, CCl3, CH3, Ph(=C6H5, phenyl) and Fc, were tested for cytotoxicity against HeLa (human cervix epitheloid), COR L23 (human large cell lung carcinoma) and platinum resistant CoLo320DM (human colorectal) and COR L23/CPR cancer cell lines. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay. Results: The mean drug concentration from 3 experiments causing 50% cell growth inhibition, (IC50) values, varied between 4.5 and 85.0 mu mol dm(-3), with the CF3-containing beta-diketone being the most active. Drug activity was inversely proportional to the formal reduction potential, E-o', of the ferrocenyl group, and dependent on the R group in the general beta-diketone structure. The CF3 complex was more cytotocic than cisplatin inter alia against platinum-resistant cell lines, and at least eight times more reactive against cancer cell lines than against PHA (phytohaemagglutinin)-stimulated lymphocyte cultures. Conclusion: A drug activity-structural relationship exists in that ferrocenyl drugs with halogen substituents chains are more cytotoxic. Compounds with higher ferrocenyl group formal reduction potential and stronger acid strength (i.e. smaller pK(a) value) are more cytotoxic.