Mustards, reactions with proteins

The reactions with thiol groups (e.g., those that are found in proteins) form an alkylarsine sulfide. Mustard gas, at the same LCtso, induces vesication, whereas Lewisite does not. Apparently, Lewisite is more irritating initially to the pulmonary systems than mustard. The hydrolysis products are more persistent in soil in comparison with mustard. In ambient air. Lewisite is about 10 times more volatile than mustard. 

Assays for several other potential urinary analytes have been developed, but the analytes have yet to be confirmed in human exposed samples. N7-(2-hydroxyethylthioethyl) guanine is a breakdown product from alkylated DNA that has been observed in animal studies. Fidder et al. (1996a) developed both a GC-MS method that requires derivatization of the analyte and also a LC-MS-MS method that can analyze the compound directly. Other possible urinary analytes are an imidazole derivative formed from the reaction of sulfur mustard with protein histidine residues (Sandelowsky et al., 1992) and sulfur mustard adducts to metallothionien (Price et al., 2000). 

Agents acting by an Sn 2 mechanism can be more selective in the nucleophile sites they attack, since they form transition complexes with some molecules more readily than with others. Other agents in vivo may, because of their chemical structure, concentrate in certain areas, giving effects not predicted from model experiments. This is the case with dimethylmyleran, a sulphonoxyalkane, quite unreactive to nucleophiles in vitro, but quite toxic in vivo. Presumably this is due to its reaction with nucleophiles, which are in the lipid phase where it concentrates. Similarly the biological activity of the aromatic nitrogen mustard chlorambucil is considerably influenced by complexing with serum proteins. 

Most of the work on skin biochemistry in relation to sulphur mustard burns was stimulated by the enzyme theory of vesication (Peters, 1936). It remains to be determined whether (a) injury is primarily dependent upon a direct reaction of the agents with one or a few specific and highly important proteins or other molecular species, or (b) there is a more or less random reaction of the vesicant with reactive groups of numerous proteins producing the observed pathological effects. 

The TLC method was developed for amino acids therefore, in principle, it is equally applicable to peptides. Peptides, such as amino acids, are generally hydrophilic. There are, however, limits to this analogy. Dinitrophenylamino acid derivatives (DNP amino acids) and phenylthiohydantoin derivatives (PTH amino acids) are obtained when reaction of peptides or proteins with dinitrofluorobenzene or phenyl mustards are properly degraded. Their separation from reaction mixtures and their identification are considerable practical importance because they constitute essential steps... 

More recently Herriott, Anson and Northrop (366) have found that chemically pure mustard reacts readily at room temperatures in aqueous solution with many different proteins. When the reaction mixture is kept at pH 5.5-6.0 the carboxyl groups are esterified, as indicated by... 

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