On the selectivity of superoxide dismutase mimetics and its importance in pharmacological studies

Abstract

The list of pathophysiological conditions associated with the overproduction of superoxide expands every day. Much of the knowledge compiled on the role of this radical in disease has been gathered using the native superoxide dismutase enzyme and, more recently, by the use of superoxide dismutase knockout models or transgenic models that overexpress the various isoforms of the enzyme. Although the native enzyme has shown promising anti-inflammatory properties in both preclinical and clinical studies, there were drawbacks and issues associated with its use as a therapeutic agent and pharmacological tool. Based on the concept that removal of superoxide modulates the course of inflammation, 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 have been designed. In this review, we will discuss the advances made using various superoxide dismutase mimetics that led to the proposal that superoxide (and/or the product of its interaction with nitric oxide, peroxynitrite) is an important mediator of inflammation, and to the conclusion that superoxide dismutase mimetics can be utilized as therapeutic agents in diseases of various etiologies. The importance of the selectivity of such compounds in pharmacological studies will be discussed.

Figure 1

Superoxide and SOD in health and disease. Endogenous SODs are critical in keeping superoxide under tight control. In diseases, there is an imbalance between the amount of superoxide formed and in the ability of the enzymes to remove it (activity of the enzyme is reduced).

Figure 2

Relative roles of SOD isoforms in disease. SOD isoforms are well compartmentalized inside the cell (SOD1, cytoplasm; SOD2 in the mitochondria) and in the extracellular space (SOD3). The involvement of the three isoforms in several pathological conditions has been unravelled by modulating the expression of the three enzymes using knockout and transgenic models.

Figure 3

Impact of superoxide generation in inflammation. Excessive production of superoxide can lead to inflammation through various pathways, including the generation of destruction of beneficial nitric oxide (NO) and simultaneous generation of cytotoxic and proinflammatory peroxynitrite (ONOO⁻).

Figure 4

Structure of different classes of superoxide scavengers.

Figure 5

Effect of SOD mimic M40403 on superoxide production from human neutrophils. Spin-trapping measurements were performed using the spin trap DEPMPO, 10 mM, with 0.4 M PMN stimulated with PMA, 200 ng/ml. The spectra shown were recorded 30 min post activation. (a) Control-activated PMNs; (b) in the presence of 2.5 M M40403. EPR spectra were recorded in a flat cell on a Bruker ESP300 spectrometer, using a TM110 cavity with 100 kHz modulation frequency.

Figure 6

Structures of Mn(II)-based selective SODm (for example, M40403).

Figure 7

Therapeutic opportunities for SODm.