COMPARISON OF HALOGENATED ACIDS 277 



inhibiting glycolysis (Lundsgaard, 1932), and have a low degree of toxicity 

 (Morrison, 1946). The effect of the vicinal carboxylate or carboxamide 

 group on the alkylating activity of the halogen atom is quite definite here, 

 and even the propionate derivatives are mostly ineffective. Such relation- 

 ships are, of course, not seen when a nonalkylating mechanism is responsible 

 for the inhibition, as in the competition of various amides with acetaldehyde 

 for alcohol dehydrogenase (Woronick, 1961). Here the size and the van der 

 Waals' forces of the halogen or aliphatic groups are more important in 

 determining the potency of the inhibition. 



Esters of the Haloacetates 



The methyl and ethyl esters of bromoacetic and iodoacetic acids have 

 been used to facilitate' penetration, the early work apparently being based 

 of the assumption that the esters are hydrolyzed to the active inhibitors 

 within the cells. The important questions one must ask first are the follow- 

 ing. Are these esters reactive with SH groups? How readily are the esters 

 hydrolyzed? Are there enzymes within cells to catalyze this hydrolysis and, 

 if so, how active are they? Is there evidence that the EM pathway can be 

 blocked, or that the esters can induce rigor in muscle? There is no doubt 

 that some of these esters are very potent metabolic inhibitors and toxic 

 agents. Ethyl bromoacetate is very toxic and irritant to the skin and for 

 this reason was used at the beginning of World War I as a war gas and 

 studied at the Kaiser- Wilhelm Institute (Wachtel, 1920). Administration 

 of 0.2 ml (1.4 mmoles) subcutaneously to cats leads to death within 1 hr, 

 the toxic symptoms being referable to the central nervous system and death 

 resulting from respiratory paralysis. The lethal dose for man by inhalation 

 is 5000 ct.* Several of the esters have been used commercially as food pre- 

 servatives, and are often potent bacteriostatic and fungistatic agents; for 

 example, several esters of bromoacetate inhibit the growth of Torula utilis 

 50% at concentrations around 0.003 mM (Hansen, 1956 a). 



The pattern of enzyme inhibition by the esters of iodoacetate (Table 

 1-45) is not the same as for iodoacetate, and some SH enzymes are quite 

 resistant to the esters. On the other hand, enzymes such as yeast hexo- 

 kinase, heart succinate oxidase, milk xanthine oxidase, and yeast alcohol 

 dehydrogenase are inhibited more strongly by the esters than by iodoace- 

 tate. It seems that 3-PGDH is not as sensitive to the esters. However, the 

 results obtained on enzymes must be interpreted in light of the spontaneous 

 hydrolysis of these esters. Bergmann and Shimoni (1953) found that the 

 methyl and ethyl esters of the haloacetates are hydrolyzed rapidly, those 



* This expresses exposure in terms of concentration and duration: c = concen- 

 tration as cubic millimeters of ester per cubic meter of air, and t = exposure time 

 in min. 



