Antineoplastic Activity of Polyaspartamide-Ferrocene Conjugates

The ferrocene/ferricenium redox system plays a significant role in biological oxidation, reduction and free-radical reactions. Of particular interest are the findings of earlier investigations which showed certain water-soluble ferricenium salts to possess appreciable antiproliferative activity against various murine tumor lines and a xenografted human colorectal adenocarcinoma. Solubility in water, a prerequisite for efficacious transport and dissipation in central circulation, was then proposed as a principal requirement for the ferrocene complex system to exert antineoplastic activity irrespective of the oxidation state in which it is administered. In order to shed more light on this question, we decided to investigate the antiproliferative properties of polymer-ferrocene conjugates containing the metal complex in the non-oxidized (ferrocene) form while fulfilling the critical requirement of water solubility. To this end, five selected, watersoluble conjugates, synthesized by reversible coupling of 4-ferrocenylbutanoic acid to variously structured polyaspartamides featuring pendant primary amino groups as coupling sites, were tested in vitro against cultured HeLa cells at concentrations up to 50 μg Fe ml-1. Optimal antiproliferative activities, with IC50 in the range of 2-7 μg Fe ml-1, were determined for three compounds possessing tertiary-amine functions susceptible to protonation at physiological pH. Lower activities (IC50 = 45-60 μg Fe ml-1) were demonstrated for two poly(ethylene oxide)-containing conjugates. However, no reasonable structure-performance relationships can be derived at this stage from the small number of compounds tested. © 1998 John Wiley & Sons, Ltd.