A variety of industrial chemicals, plant and microbial secondary metabolites, and oxidative stress byproducts contain electrophilic centers that react with nucleophilic sites in proteins. We have previously found that two distinct bifunctional electrophiles�diethylacetylene dicarboxylate and divinyl sulfone�are considerably more toxic than monofunctional analogs. Here, we compared the toxicity of a panel of eight structurally diverse bifunctional electrophiles with their monofunctional analogs in order to quantify the enhancement in toxicity afforded by molecules with two electrophilic centers. Results of toxicity assays by growth inhibition in yeast and mammalian cells show a marked increase in toxicity, with bifunctional electrophiles ranging from 5-20 fold more toxic than monofunctional analogs. These differences are even more pronounced in yeast, where the bifunctional electrophiles range from 100-1000 fold more potent than analogous molecules. Each of the bifunctional electrophiles is capable of cross-linking recombinant cytosolic thioredoxin (Trx2) from baker's yeast in vitro; to varying degrees, Trx2 is also a target of these molecules in treated yeast cells. Taken together, our results show a general trend that bifunctional protein cross-linkers, despite having just twice the reactivity, exhibit considerably greater toxicity than simple protein alkylating agents.

Pronounced toxicity of bifunctional electrophiles in comparison to monofunctional structural analogs

245th National Meeting (2013)

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