Design synthesis of a sequence-specific DNA cleaving molecule. (Distamycin-EDTA)iron(II)

The sequence-dependent recognition of nucleic acids by proteins and small molecules is important in the regulation of many biological processes. A large class of these molecules are bifunctional in nature, combining a chemically reactive moiety with a DNA binding unit. One such molecule is the naturally occurring antitumor antibiotic bleomycin, which binds to and cleaves DNA sequence specifically in a reaction that depends on Fe(II) and oxygen. Recently we reported the synthesis of a DNA binding-DNA cleaving molecule, methidiumpropyl-EDTA (MPE). This bifunctional molecule has the DNA intercalator, methidium, tethered to a metal chelator, EDTA. MPE·Fe(II) cleaves double helical DNA in the presence of dithiothreitol (DTT) with efficiencies comparable to those of bleomycin·Fe(Il)/DTT. Unlike bleomycin·Fe(II), MPE·Fe(II) cleaves DNA non-sequence-specifically, consistent with solution studies demonstrating that the intercalator methidium has no overall base composition specificity