1,2,5,6-Diepoxyhexane and 1,2,7,8-Diepoxyoctane Cross-Link Duplex DNA at 5‘-GNC Sequences

• Published in: Chemical research in toxicology 1996-09, Vol.9 (6), p.994-1000
• Main Authors: Yunes, Michael J, Charnecki, Sara E, Marden, Jennifer J, Millard, Julie T
• Format: Article
• Language: English
• Subjects: Carcinogens - chemistry; Cross-Linking Reagents - chemistry; DNA - chemistry; Electrophoresis, Polyacrylamide Gel; Epoxy Compounds - chemistry; Oligonucleotides - chemistry; Structure-Activity Relationship
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx960059c

The carcinogenicity of epoxide compounds has been attributed to covalent binding to DNA. Whereas monoepoxides form only monoadducts, diepoxides can form both monoadducts and interstrand cross-links. The latter are believed to be the more significant cytotoxic lesions as diepoxides are frequently more carcinogenic and mutagenic than their monoepoxide analogues. We therefore examined the relative DNA interstrand cross-linking capabilities of several diepoxides with respect to chain length, molecular flexibility, reported carcinogenic potential, and DNA sequences targeted. Using denaturing polyacrylamide gel electrophoresis, we found that 1,2,5,6-diepoxyhexane and 1,2,7,8-diepoxyoctane share the 5‘-GNC target sequence previously found for 1,2,3,4-diepoxybutane [Millard, J. T., and White, M. M. (1993) Biochemistry 32, 2120−2124] and that the efficiency of cross-linking this sequence may reflect carcinogenicity. 1,2,5,6-Diepoxycyclooctane, the biologically inactive rigid analogue of 1,2,5,6-diepoxyhexane, was found to be a poor cross-linker of all DNA sequences examined. Moreover, increasing the diepoxyalkane chain length did not result in enhanced cross-linking ability.