TRIPLEX-DIRECTED INTERSTRAND DNA CROSS-LINKING BY DIAZIRIDINYLQUINONE-OLIGONUCLEOTIDE CONJUGATES

Tripler-forming oligonucleotides (TFOs) bind in the major groove to sp ecific double-helical DNA sequences and have been shown to inhibit the function of targeted genes. Diaziridinylquinones are bifunctional alk ylating agents that can form interstrand cross-links in DNA at 5'-GNC sites. To demonstrate the feasibility of targeted interstrand cross-li nking, a diaziridinylquinone-TFO conjugate was prepared from a diaziri dinylquinone intermediate bearing an activated ester linker. The first demonstration of tripler-directed interstrand DNA cross-linking by a single targeted bifunctional alkylating agent is described. Up to 38% interstrand cross-linking was observed at pH 6.2.