We propose to synthesize and study new multifunctional DNA binding small molecules. (1) We will synthesize bis(monoazido)methidium as a photoaffinity probe of the polyintercalator BMSp binding sites in plasmid DNA. (2) We will characterize the new bifunctional molecule methidiumpropyl-EDTA-Fe(II) (MPE-Fe(II) which cleaves double helical DNA efficiently analogous to the antitumor antibiotic bleomycin. Unlike bleomycin which cleaves DNA sequence specifically, MPE-Fe(II) has no base composition specificity and has proven to be a useful footprinting tool for mapping antibiotic binding sites on heterogeneous DNA. (3) We will synthesize high affinity sequence-specific DNA binding molecules bis(distamycin)C8 and bis(distamycin)phenoxazone and importantly characterize their sequence specificity and binding site size on heterogeneous DNA by footprinting with MPE.Fe(II). (4) We will then attach covalently to distamycin bis(distamycin)C8 and bis(distamycin)phenoxazone one (or two) EDTA.Fe(II) moieties to create a prototype set of rationally designed sequence-specific single (and double) strand DNA cleaving agents. These studies may provide new data for ligant/drug design with regard to the nucleic acid receptor, and new tools for probing nucleic acid structure and drug/nucleic acid interactions important for any understanding of the mechanism of drug action of DNA binding molecules.
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