Antineoplastic activity of polyaspartamide-ferrocene conjugates

The ferrocene/ferricenium redox system plays a significant role in biologic al oxidation, reduction and free-radical reactions. Of particular interest are the findings of earlier investigations which showed certain water-solub le ferricenium salts to possess appreciable antiproliferative activity agai nst various murine tumor lines and a xenografted human colorectal adenocarc inoma, Solubility in water, a prerequisite for efficacious transport and di ssipation in central circulation, was then proposed as a principal requirem ent for the ferrocene complex system to exert antineoplastic activity irres pective of the oxidation state in which it is administered. In order to she d more light on this question, we decided to investigate the antiproliferat ive properties of polymer-ferrocene conjugates containing the metal complex in the non-oxidized (ferrocene) form while fulfilling the critical require ment of water solubility, To this end, five selected, water-soluble conjuga tes, synthesized by reversible coupling of 4-ferrocenylbutanoic acid to var iously structured polyaspartamides featuring pendant primary amino groups a s coupling sites, were tested in vitro against cultured HeLa cells at conce ntrations up to 50 mu g Fe ml(-1). Optimal antiproliferative activities, wi th IC50 in the range of 2-7 mu g Fe ml(-1), were determined for three compo unds possessing tertiary-amine functions susceptible to protonation at phys iological pH, Lower activities (IC50=45-60 mu g Fe ml(-1)) were demonstrate d for two poly(ethylene oxide)-containing conjugates, However, no reasonabl e structure-performance relationships can be derived at this stage from the small number of compounds tested, (C) 1998 John Wiley & Sons, Ltd.