Structure–Activity Studies and the Design of Synthetic Superoxide Dismutase (SOD) Mimetics as Therapeutics

Publisher Summary This chapter describes highly stable Mn(II) complexes that possess high superoxide dismutase (SOD) activity—the two key attributes for an efficient SOD mimetic-based drug. Key to success in designing and synthesizing highly stable and highly active SOD mimetics is the development of a detailed understanding of the mechanism of action of this class of SOD mimetics, and the subsequent development of a computer-aided design (CAD) paradigm based on molecular mechanics (MM) that makes it possible to study and screen a large number of possible structures prior to embarking on complicated syntheses of highly substituted and constrained ligands. An understanding of the details of the mechanism of action of synthetic superoxide dismutase catalysts has made it possible to devise a computer modeling paradigm that allows one to design highly substituted (and hence highly stable) complexes that possess high catalytic activity. Molecular mechanics calculations have made it possible to correctly predict how substituents and their stereochemistry affect the energetics of ligand folding and thus catalytic activity. The chemistry presented for designing and synthesizing core catalyst structures optimized for stability and catalytic activity, are amenable to the construction of complexes that have pendant functionality; for example, alcohols, amines, amides, esters, acids, etc.