364 3. .V-ETHYLMALEIMIDE 



can augment contractility under certain circumstances, iV-ethylmaleimide 

 is the only SH reagent with this property. Furthermore, it is quite potent, 

 acting at 0.1 mM. Only hypodynamic myocardium is stimulated. The 

 R — CH=CH — CO — R' grouping was thought to be responsible for this 

 action. A^-Ethylmaleimide at 0.1 mM lowers the electrical potential across 

 frog skin and from the changes in resistance it was suggested that, as with 

 the mercurials, the reactive SH groups lie within the anion-transporting 

 pores, the inhibitors acting sterically to impede ion flow (Janacek, 1962). 



EFFECTS ON MITOSIS AND GROWTH 



The initial work on A'-ethylmaleimide was prompted by the attempt to 

 find mitotic inhibitors related to maleate, and this substance was found 

 to be one of the most potent of all the imides tested (Friedmann et at., 

 1949). Mitosis in chick fibroblast cultures is reduced 18% by 0.0004 m.M 

 iV-ethylmaleimide and the phase distribution is appreciably shifted, in- 

 dicating a metaphase inhibitor. The effects increase with concentration 

 up to 0.002 mM and then remain constant. No significant cytological ab- 

 normalities were observed. When iV-ethylmaleimide is allowed to react 

 with excess glutathione the antimitotic activity is mainly lost, but there 

 is some residual effect that was thought might be due to the adduct it- 

 self (Friedmann et al., 1952 b). The whole problem of the mechanism 

 involved here remains to be solved and it is by no means certain that SH 

 group reaction is the essential factor. Although it was stated that succin- 

 imide is inactive (Friedmann et al, 1949), it increases the number of cells 

 in metaphase very significantly (from 27% to 41%), although mitosis 

 in not greatly depressed. Furthermore, the very high potency indicates 

 some very specific action; indeed, it is surprising that there is enough N- 

 ethylmaleimide to produce an effect since at concentrations around 0.001 

 mM one would expect a large fraction to be reacted with nonfunctional 

 components. In fact, the medium contained 0.15 mM glutathione, which 

 would be expected to inactivate most of the iV-ethylmaleimide before it 

 had the opportunity to enter the cell (Friedmann, 1952). It is also surprising 

 that no further work has been done on this interesting antimitotic effect. 



iV-Ethylmaleimide is potently bacteriostatic, inhibiting growth of Staphy- 

 lococcus aureus and Escherichia coli 50% at 0.025 and 0.016 mM, respec- 

 tively (Marrian et al., 1953). Terminal division of Erwinia, one of the En- 

 terobacteriaceae, triggered with Ca++ or pantoate is completely inhibited by 

 3 mM xV-ethylmaleimide (Grula and Grula, 1962). Yeast, on the other 

 hand, is much more resistant, 50% inhibition of growth being produced 

 by 8 mM A^-ethylmaleimide (Loveless et al., 1954). The sensitivity of 

 bacteria to X-radiation and y-radiation is markedly increased by A'-ethyl- 

 maleimide (Bridges, 1960, 1961). It was stated that 1 mM iV-ethylmaleimide 



