SEQUENCE SPECIFIC ALKYLATION OF DNA

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Polyamides containing imidazole and pyrrole amino acids have the ability to bind an predetermined sequence of duplex DNA. This research proposal seeks to exploit this phenomenon and create synthetic molecules capable of not only recognizing any predetermine sequence of duplex DNA but also capable of introducing DNA damage in a predetermine location. To accomplish this, synthetic hybrids are proposed which covalently link derivatives of the antitumor, antibiotic class of natural products the pyrrolo(l,4)benzodiazepines with various polyamides. The pyrrolo(l,4)benzodiazepines have the ability to bind exclusively to the minor groove of duplex DNA and alkylate guanine residues. Therefore, it is predicted that coupling polyamides to various pyrrolo(l,4)benzodiazepines will create a synthetic conjugate capable of recognizing any predetermined sequence of duplex DNA, as dictated by the polyamide portion of the molecule, and introduce DNA alklation at neighboring guanine residues.