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Chapter category: Ischemia-Reperfusion
Development of Manganese(II)-Based Superoxide Dismutase Mimics
Chapter authors:
Daniela Salvemini, Dennis P. Riley, Salvatore Cuzzocrea
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The list of patho-physiological conditions associated with the over-production of super
oxide anion expands every day. The most exciting realization is that there appears to be
a commonality to the tissue injury observed in various disease states; and that superoxide
anion, produces tissue injury (and associated inflammation) in all tissues in similar ways.
Tissue injury and inflammation form the basis of many disease pathologies: ischemia and
reperfusion injuries, radiation injury, hyperoxic lung damage, atherosclerosis and so forth. This
commonality provides an unique opportunity to manipulate numerous disease states with an
agent that removes superoxide anion. Much of the knowledge that has been gleaned concerning
the roles of superoxide anion in disease has been gathered using the native superoxide
dismutase enzyme and, more recently, by data generated in transgenic animals that over-express
the human enzyme. Although, the native enzyme has shown promising anti-inflammatory
properties in both preclinical and clinical studies, in a variety of diseases, there were drawbacks
and issues associated with the use of the native enzymes as therapeutic agents and as pharmacological
tools. Based on the concept that removal of superoxide anion modulates the course of
inflammation, we have pursued the concept of designing synthetic, low molecular weight
mimetics of the superoxide dismutase enzymes that could overcome some of the limitations
associated with the use of the native enzyme. The rational design and synthesis of low molecular
weight catalysts which mimic a natural enzymic function has potential for use as human
pharmaceuticals. Such synthetic enzymes (synzymes) have as a potential utility the treatment of
diseases characterized by the overproduction of a potentially deleterious molecule or foreign
gene product. The development of manganese(II)-based superoxide dismutase (SOD) mimics
and their potential utility as human pharmaceutical agents is described.
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