The effect of simple peptides on the superoxide dismutase mimetic activity and stability constants of copper complexes of some radioprotective dithioacetic acid derivatives

A series of bis(methylthio) and methylthio amino derivatives of 1-methylpyridinium- (and quinolinium)-2-dithioacetic acids has been found to have good radiation protective activity vs. a lethal dose (1000 rads) of {dollar}gamma{dollar}-radiation in mice. The copper(II) complexes of these compounds have also shown significant ability to mimic the action of superoxide dismutase (SOD) in converting the superoxide radical to {dollar}rm Hsb2Osb2{dollar} and O{dollar}sb2.{dollar} A positive correlation was found between the extent of SOD activity and the degree of radiation protection in mice with both pyridinium and quinolinium series.; To determine whether the copper complexes, which were isolated in a 1:1 ratio with the dithioacetic acid derivatives, can maintain their ability to mimic the action of SOD in the presence of simple peptides and a protein (bovine serum albumin), several methods of SOD assay were carried out, as well as spectral analyses of the complexes in the presence of peptides, and also binding studies with serum albumin. The data supported the conclusion that peptides and protein do not bind to the complexes with sufficient binding ability to interfere with the SOD mimetic activity. This finding supports the postulation of SOD mimetic activity as a mechanism of radiation protection in vivo.; Metal-binding stability constants for the pyridinium series have not been previously determined. It was of interest to determine the stability constants of these compounds with Cu(II) to see whether they were capable of forming stable complexes, which is essential if they are to exist as copper complexes in vivo in the presence of simple peptides. It was also of interest to determine if a positive correlation could be drawn between the metal-binding avidities of these compounds and their SOD mimicking activities in both pyridinium and quinolinium series. It was found that the metal-binding stability constants with Cu(II) of these compounds are greater than those of simple peptides for Cu(II) and hence they should be able to exist as stable copper complexes under cellular conditions. No correlation could be drawn between their metal-binding avidities and their radiation protection abilities and corresponding SOD mimicking activities, however.