Disulfides as Protecting Groups and Targets

The role of GSH in cellular protection (see below) means that if depleted of GSH, the cell is more vulnerable to toxic compounds. However, GSH is compartmentalized, and this compartmentalization exerts an influence on the relationship between GSH depletion or oxidation and injury. The loss of reduced GSH from the cell leaves other thiol groups, such as those in critical proteins, vulnerable to attack with subsequent oxidation, cross-linking, and formation of mixed disulfides or covalent adducts. The sulfydryl groups of proteins seem to be the most susceptible nucleophilic targets for attack, as shown by studies with paracetamol (see chap. 7), and are often crucial to the function of enzymes. Consequently, modification of thiol groups of enzyme proteins, such as by mercury and other heavy metals, often leads to inhibition of the enzyme function. Such enzymes may have critical endogenous roles such as the regulation of ion concentrations, active transport, or mitochondrial metabolism. There is... 

In contrast to these two successful reports, a somewhat sobering account of poor rewards in multistep disulfide formation is provided by the systematic exploration of the various regioselective approaches to the three disulfides of antimicrobial peptide PMP-D2 [12]. Two combinations of Cys protecting groups (Trt, Acm, Mob and Trt, Mmt, Acm) and four different routes to the target compound were evaluated. The results indicated that neither strategy was as efficient as the synthetically less demanding simultaneous oxidation of the hexathiol derived from an all-Trt protected peptide resin precursor. 

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