SEQUENCE-SPECIFIC DOUBLE-STRAND CLEAVAGE OF DNA BY BIS(EDTA-DISTAMYCIN.IRON(II)) AND EDTA-BIS(DISTAMYCIN).IRON(II)

We report the synthesis of two sequence-specific double-strand DNA cleaving molecules, bis(EDTA-distamycin·Fe^(II) (BED·Fe^(II)) and EDTA-bis(distamycin)·Fe^(II) (EBD·Fe^(II)) (Chart 1). These molecules contain two N-methylpyrrole tripeptide units coupled at the amino termini via a flexible tether with EDTA attached to one or both carboxy termini. In the presence of O_2 and dithiothreitol (DTT), nanomolar concentrations of BED·Fe^(II) and EBD·Fe^(II) cleave DNA (25 °C, pH 7.9). BED·Fe^(II) and EBD·Fe^(II) cleave pBR 322 plasmid DNA (4362 base pairs) on opposite strands to afford discrete DNA fragments. High-resolution gel electrophoresis of an end-labeled restriction fragment containing a major binding site reveals cleavage contiguous to an eight base pair sequence 5'-TTTTTATA-3'.