Pronounced toxicity differences between homobifunctional protein cross-linkers and analogous monofunctional electrophiles.

Abstract

Bifunctional electrophiles have been used in various chemopreventive, chemotherapeutic, and bioconjugate applications. Many of their effects in biological systems are traceable to their reactive properties, whereby they can modify nucleophilic sites in DNA, proteins, and other cellular molecules. Previously, we found that two different bifunctional electrophiles--diethyl acetylenedicarboxylate and divinyl sulfone--exhibited a strong enhancement of toxicity when compared with analogous monofunctional electrophiles in both human colorectal carcinoma cells and baker's yeast. Here, we have compared the toxicities for a broader panel of homobifunctional electrophiles bearing diverse electrophilic centers (e.g., isothiocyanate, isocyanate, epoxide, nitrogen mustard, and aldehyde groups) to their monofunctional analogues. Each bifunctional electrophile showed at least a 3-fold enhancement of toxicity over its monofunctional counterpart, although in most cases, the differences were even more pronounced. To explain their enhanced toxicity, we tested the ability of each bifunctional electrophile to cross-link recombinant yeast thioredoxin 2 (Trx2), a known intracellular target of electrophiles. The bifunctional electrophiles were capable of cross-linking Trx2 to itself in vitro and to other proteins in cells exposed to toxic concentrations. Moreover, most cross-linkers were preferentially reactive with thiols in these experiments. Collectively, our results indicate that thiol-reactive protein cross-linkers in general are much more potent cytotoxins than analogous monofunctional electrophiles, irrespective of the electrophilic group studied.

• Authors: Matthew K Spencer, Nikolai P Radzinski, Susmit Tripathi, Sreyan Chowdhury, Rachelle P Herrin, Naveeshini N Chandran, Abigail K Daniel, James D West
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 26 Issue 11 Pg. 1720-9 (Nov 18 2013) ISSN: 1520-5010 [Electronic] United States
• PMID: 24138115 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• Cross-Linking Reagents
• Epoxy Compounds
• Isocyanates
• Recombinant Proteins
• Mechlorethamine
• Thioredoxins

Topics

• Aldehydes (chemistry, toxicity)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cross-Linking Reagents (chemistry, toxicity)
• Epoxy Compounds (chemistry, toxicity)
• Humans
• Isocyanates (chemistry, toxicity)
• Mechlorethamine (chemistry, toxicity)
• Recombinant Proteins (biosynthesis, chemistry, genetics)
• Saccharomyces cerevisiae (drug effects, metabolism)
• Thioredoxins (chemistry, genetics, metabolism)