604 6. ARSENICALS 



The arsenoxides (R — AsO) are enzyme inhibitors and biologically active 

 because of the facility with which the arsenoxide group reacts with SH 

 groups. The remainder of the molecule generally does not participate in 

 the reaction, but serves to modify the properties of the molecule, especially 

 with regard to the penetration into cells, the adsorption to proteins, and 

 the solubility, and in addition modifies quantitatively the properties of the 

 arsenoxide group with respect to its redox potential and ionization. Thus, 

 in general, we may say that all these substances act ultimately by the same 

 basic chemical reaction, but differ in the ability to reach the thiols or en- 

 zymes within living cells and in the rate at which mercaptide formation 

 occurs. 



As is the case with inorganic arsenite, there is no agreement as to the 

 dominant form in aqueous solution, i. e., the extent of hydration. The 

 arsenoxides are usually written as E, — As=0, but it is possible that the 

 hydrated R — As(0H)2 forms are also important. If so, the vK^s must 

 be quite high and the groups should exist mainly in the un-ionized state 

 at physiological pH. Of course, acidic or basic substituent groups on the 

 benzene ring may ionize to increase the solubility and provide compounds 

 convenient to use in enzyme studies. The pentavalent phenylarsonic acids, 

 on the other hand, ionize readily, indicating that the substances exist in 

 solution mainly in the E, — AsO(OH)2 form. Some ionization constants 

 are given in Table 6-1. The preponderant form in the physiological pH 

 range is thus the R — AsOgH" anion, with variable and appreciable fractions 

 in the R — As03= form. These values may be compared with those for 

 inorganic arsenic acid: p^^ = 2.30, ])K^ = 4.40, and pK^ = 9.22. 



The phenylarsonous acids (or phenylarsenoxides) and the phenylarsonic 

 acids form oxidation-reduction systems whose redox potentials are diffi- 

 cult to determine because of the slow attainment of equilibrium. Since it 

 is assumed that most arsonates are active only after reduction, and since 

 the question of the oxidation of the arsonous acids in tissue preparations 

 is often pertinent, the rates of oxidation or reduction would be useful to 

 know, as well as the thermodynamic equilibria when coupled with other 

 redox systems. For example, it has been postulated that the activity of 

 the phenylarsonates may be related to the speed at which they are reduced 

 (Cohen et at., 1932). The rates of reduction are technically difficult to 

 measure but the bimolecular rate constans for the oxidation of various 

 phenylarsonous acids by cystine were determined (see accompanying 

 tabulation). It may be mentioned that no correlation between these rates 

 and the toxicity of the phenylarsonic acids was found, which is not sur- 

 prising inasmuch as the rates of oxidation of the arsonous acids would 

 bear no necessary relation to the rates of reduction of the corresponding 

 arsonic acids. It is important to remember, however, that reduction can 

 take place quite readily in biological systems, often by thiols with which 



