JS-K and related nitric oxide (NO)-releasing O2-arylated diazeniumdiolate prodrugs have demonstrated pronounced cytotoxicity and antitumorigenic properties in a variety of cancer models both in vitro and in vivo.  Aryl bis(diazeniumdiolates) were created with the purpose of doubling the payload of NO, effectively delivering 4 mols of NO/ mol of compound. These compounds cause pronounced protein glutathionylation, in contrast to their monovalent counterparts. This glutathionylation is independent of NO generation. Serving as bivalent electrophiles, (bis)diazeniumdiolates can irreversibly crosslink a molecule of glutathione (GSH) to a protein thiol through an aromatic linker. The results provide a previously unrecognized component of the multifaceted mechanism of action of bivalent electrophiles of the arylated diazeniumdiolate class, adding to the list of established pathways of GSH depletion, NO-mediated toxicity including classical glutathionylation, and protein S-arylation seen with their monovalent counterparts such as JS-K.

Crosslinking glutathionylation, a novel thiol modification induced by compounds of the diazeniumdiolate class

245th National Meeting (2013)

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