The project involves an investigation of the ability of macrocyclic polythiaethers to complex and mobilize heavy-metal ions in biological systems. A series of such ligands has been synthesized containing two, four, or six sulfur atoms in the ring with ring sizes ranging from twelve to twenty-eight atoms. This work is currently being extended to include derivatized compounds with selected functional groups substituted on the ring. The thermodynamic stability constants of these ligands complexing with Cu(II), Hg(II), and other selected metal ions are being determined in vitro in order to correlate ligand structure with metal ion selectivity. Kinetic studies of the more strongly complexing ligands reacting with Cu(II) and Hg(II) are also being undertaken using the stopped-flow and temperature-jump relaxation techniques. These studies are aimed at establishing the step-wise mechanism involved in these complexation reactions and the kinetic variations induced by structural and matrix effects. Single-crystal X-ray crystallographic studies are also being carried out to provide definitive structual information. Finally, in vivo pharmacological studies are being conducted to determine the ability of selected polythiaether ligands to promote Hg(II) elimination as well as to establish the toxicological effects of these compounds, their retention and physiological distribution, and their influence upon internal redistribution of Hg(II).